AMINOPYRIDAZINONE COMPOUNDS AS PROTEIN KINASE INHIBITORS

COMPOSES AMINOPYRIDAZINONE A UTILISER EN TANT QU'INHIBITEURS DE PROTEINES KINASES

English Abstract

The present disclosure provides a compound of formula (I) and the use thereof for the therapeutic treatment of human cancers including B-cell lymphoma and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis.

French Abstract

La présente invention concerne un composé de formule (I) et son utilisation pour le traitement thérapeutique de cancers humains, notamment le lymphome B et de maladies auto-immunes telles que la polyarthrite rhumatoïde, le lupus érythémateux systémique et la sclérose en plaques.

Claims

- 77 -
What is claimed is:
1. A compound of formula (I), tautomers, rotamers, geometric isomers,
diastereomers, racemates, and enantiomers, a pharmaceutically acceptable salt,
a
solvate, or a hydrate thereof,
Image
wherein A is selected from the group consisting of CR0 and N; and wherein R0
is selected from the group consisting of hydrogen, halogen, and unsubstituted
or
substituted alkyl;
R a, R b, R c and R d are independently selected from the group consisting of
hydrogen, halogen, hydroxyl, nitro, cyano, unsubstituted or substituted alkyl,
and
unsubstituted or substituted alkoxyl;
B is selected from the group consisting of hydrogen, unsubstituted or
substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or
substituted
heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or
substituted
heteroaryl;
L is unsubstituted or substituted alkylene, or absent; and
Y is selected from the group consisting of unsubstituted or substituted
cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or
substituted
aryl, and unsubstituted or substituted heteroaryl.
2. The compound of claim 1, a pharmaceutically acceptable salt, a solvate,
or a
hydrate thereof, wherein A is selected from the group consisting of CH, CF,
CCI and
N.

- 78 -
3. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein at least one of R a, R b, R c and R d is
selected from the
group consisting of hydrogen, F, CI, and methoxyl.
4. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein R a, R b, R c and R d are hydrogen.
5. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein B is unsubstituted or substituted C1-C6 alkyl.
6. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein B is unsubstituted or substituted aryl.
7. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein B is unsubstituted or substituted phenyl.
8. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein B is phenyl substituted with at least one member

selected from the group consisting of halogen, cyano, nitro, hydroxyl,
unsubstituted
or substituted alkyl, unsubstituted or substituted alkoxy, -NR1R2, -C(O)R3, -
C(O)OR4,
-C(O)NHR5, and -S(O)2R6;
wherein R1 and R2 are independently selected from the group consisting of
hydrogen, unsubstituted or substituted alkyl, -C(O)R7, -C(O)OR8, -C(O)NHR9,
and
-S(O)2R13; and wherein R3, R4, R5, R6, R7, R8, R9, and R10 are independently
selected
from the group consisting of unsubstituted or substituted alkyl, unsubstituted
or
substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl,
unsubstituted or
substituted aryl, and unsubstituted or substituted heteroaryl.
9. The compound of claim 8, a pharmaceutically acceptable salt, a solvate,
or a
hydrate thereof, wherein B is phenyl substituted with at least one member
selected
from the group consisting of F, CI, and methoxyl.


-79-

10. The compound of claim 8, a pharmaceutically acceptable salt, a solvate,
or a
hydrate thereof, wherein B is phenyl substituted with two F.
11. The compound of claim 8, a pharmaceutically acceptable salt, a solvate,
or a
hydrate thereof, wherein B is phenyl substituted with two Cl.
12. The compound of claim 8, a pharmaceutically acceptable salt, a solvate,
or a
hydrate thereof, wherein B is phenyl substituted with one CI and one F.
13. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein L is absent.
14. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein L is methylene.
15. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein Y is selected from the group consisting of
unsubstituted
or substituted piperidinyl, unsubstituted or substituted phenyl, unsubstituted
or
substituted bicyclo[3.2.1]octanyl, unsubstituted or substituted azetidinyl,
and
unsubstituted or substituted pyrrolidinyl.
16. The compound of claim 15, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein Y is substituted with at least one member selected
from the
group consisting of halogen, -CN, -C(O)R11, -NHC(O)R12, -S(O)2R13, and -
NHS(O)2R14; and wherein R11, R12, R13, and R14 are independently selected from
the
group consisting of unsubstituted or substituted alkyl, unsubstituted or
substituted
cycloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted

cycloalkenyl, and unsubstituted or substituted alkynyl.

- 80 -
17. The compound of claim 15, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein Y is substituted with at least one member selected
from the
group consisting of F, CN,-C(O)CH=CH2,
-C(O)CH=CHCH2N(CH3)2, -NHC(O)CH=CH2, -C(O)CH=CHCH2N(CH3)(COOC(CH3)3;
-C(O)CH=CHCH2NH(CH3), -C(O)CH2CH3, -C(O)CH2CH2CH3, Image
-C(O)CH2CH2Cl, Image -C(O)CH2CN, Image
Image
18. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein the compound has more R-form than S-form.
19. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein the compound has more S-form than R-form.

- 81 -
20. The compound
of claim 1 or 2, a pharmaceutically acceptable salt, a solvate,
or a hydrate thereof, wherein the compound is of formula (II):
Image
wherein X1, X2, X3, X4, and X5 are independently selected from the group
consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or
substituted
alkyl, unsubstituted or substituted alkoxy, -NR1R2, -C(O)R3, -C(O)OR4, -
C(O)NHR5,
and -S(O)2R6;
R1 and R2 are independently selected from the group consisting of hydrogen,
unsubstituted or substituted alkyl, -C(O)R7, -C(O)OR8, -C(O)NHR9, and -
S(O)2R13;
and wherein R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected
from the
group consisting of unsubstituted or substituted alkyl, unsubstituted or
substituted
cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or
substituted
aryl, and unsubstituted or substituted heteroaryl;
R a is selected from the group consisting of hydrogen, halogen, hydroxyl,
nitro,
cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted
alkoxyl;
W is selected from the group consisting of halogen, hydroxyl, unsubstituted or

substituted alkyl, and unsubstituted or substituted alkoxyl; wherein two W may

combine with an atom or atoms to which they are attached to form unsubstituted
or
substituted C3-12 cycloalkyl, unsubstituted or substituted 3- to 12- membered
heterocyclic, unsubstituted or substituted C6-12 aryl, or unsubstituted or
substituted 5-
to 12- membered heteroaryl;
L is unsubstituted or substituted alkylene, or absent;
m = 0, 1, 2, or 3;


-82-

p = 1, 2, or 3;
q = 0, 1, or 2;
s = 0, 1, 2, or 3; and
Z is selected from the group consisting of -NHC(O)R12 and -NHS(O)2R14; and
wherein R12 and R14 are independently selected from the group consisting of
unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl,
unsubstituted or substituted alkenyl, unsubstituted or substituted
cycloalkenyl, and
unsubstituted or substituted alkynyl.
21. The compound
of claim 1 or 2, a pharmaceutically acceptable salt, a solvate,
or a hydrate thereof, wherein the compound is of formula (III):
Image
wherein X1, X2, X3, X4, and X5 are independently selected from the group
consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or
substituted
alkyl, unsubstituted or substituted alkoxy, -NR1R2, -C(O)R3, -C(O)OR4, -
C(O)NHR5,
and -S(O)2R6;
R1 and R2 are independently selected from the group consisting of hydrogen,
unsubstituted or substituted alkyl, -C(O)R7, -C(O)OR8, -C(O)NHR9, and -
S(O)2R10;
and wherein R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected
from the
group consisting of unsubstituted or substituted alkyl, unsubstituted or
substituted
cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or
substituted
aryl, and unsubstituted or substituted heteroaryl;
R a is selected from the group consisting of hydrogen, halogen, hydroxyl,
nitro,

- 83 -
cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted
alkoxyl;
W is selected from the group consisting of halogen, hydroxyl, unsubstituted or

substituted alkyl, and unsubstituted or substituted alkoxyl; wherein two W may

combine with an atom or atoms to which they are attached to form unsubstituted
or
substituted C3-12 cycloalkyl, unsubstituted or substituted 3- to 12- membered
heterocyclic, unsubstituted or substituted C6-12 aryl, or unsubstituted or
substituted 5-
to 12- membered heteroaryl;
L is unsubstituted or substituted alkylene, or absent;
m = 0, 1, 2, or 3;
p = 1, 2, or 3;
q = 0, 1, or 2;
s = 0, 1, 2, or 3; and
Z is selected from the group consisting of CN, -C(O)R11, and -S(O)2R13; and
wherein R11, and R13 are independently selected from the group consisting of
unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl,
unsubstituted or substituted alkenyl, unsubstituted or substituted
cycloalkenyl, and
unsubstituted or substituted alkynyl, or
Z is selected from the group consisting of CN,-C(O)CH=CH2, -
C(O)CH=CHCH2N(CH3)2, -C(O)CH=CHCH2N(CH3)(COOC(CH3)3;
-C(O)CH=CHCH2NH(CH3), -C(O)CH2CH3, -C(O)CH2CH2CH3, Image
-C(O)CH2CH2CI, Image -C(O)CH2CN, Image
Image


-84-

Image
22. The compound of claim 21, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein Z is selected from the group consisting of CN,-
C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CH=CHCH2N(CH3)(COOC(CH3)3;
-C(O)CH=CHCH2NH(CH3), -C(O)CH2CH3, -C(O)CH2CH2CH3, Image
-C(O)CH2CH2Cl, Image -C(O)CH2CN, Image
Image


-85-

23. The compound of claim 1 or 2, a pharmaceutically acceptable salt, a
solvate,
or a hydrate thereof, wherein the compound is of formula (IV):
Image
wherein X1, X2, X3, X4, and X5 are independently selected from the group
consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or
substituted
alkyl, unsubstituted or substituted alkoxy, -NR1R2, -C(O)R3, -C(O)OR4, -
C(O)NHR5,
and -S(O)2R6;
R1 and R2 are independently selected from the group consisting of hydrogen,
unsubstituted or substituted alkyl, -C(O)R7, -C(O)OR8, -C(O)NHR9, and -
S(O)2R10;
and wherein R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected
from the
group consisting of unsubstituted or substituted alkyl, unsubstituted or
substituted
cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or
substituted
aryl, and unsubstituted or substituted heteroaryl;
W is selected from the group consisting of halogen, hydroxyl, cyano,
unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxyl;
m = 0, 1, 2, or 3; and
Z is selected from the group consisting of -NHC(O)R12, and -NHS(O)2R14; and
wherein R12, and R14 are independently selected from the group consisting of
unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl,
unsubstituted or substituted alkenyl, unsubstituted or substituted
cycloalkenyl, and
unsubstituted or substituted alkynyl.

- 86 -
24. The compound of
claim 1 or 2, a pharmaceutically acceptable salt, a solvate,
or a hydrate thereof, wherein the compound is of formula (V):
Image
wherein X1, X2, X3, X4, and X5 are independently selected from the group
consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or
substituted
alkyl, unsubstituted or substituted alkoxy, -NR1R2, -C(O)R3, -C(O)OR4, -
C(O)NHR5,
and -S(O)2R6;
R1 and R2 are independently selected from the group consisting of hydrogen,
unsubstituted or substituted alkyl, -C(O)R7, -C(O)OR8, -C(O)NHR9, and -
S(O)2R10;
and wherein R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected
from the
group consisting of unsubstituted or substituted alkyl, unsubstituted or
substituted
cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or
substituted
aryl, and unsubstituted or substituted heteroaryl;
Ra is selected from the group consisting of hydrogen, halogen, hydroxyl,
nitro,
cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted
alkoxyl;
W is selected from the group consisting of halogen, hydroxyl, cyano,
unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxyl;
m = 0, 1, 2, or 3;
p = 1 or 2;
s = 0, 1, 2, or 3;
Z1 is selected from the group consisting of hydrogen, halogen, cyano, and
unsubstituted or substituted alkyl; and

- 87 -
Z2 and Z3 are independently selected from the group consisting of hydrogen,
unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl,
unsubstituted or substituted heterocycloalkyl, -CH2OR15, and -CH2NR16R17;
wherein R15 and R16 are independently selected from the group consisting of
hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted
cycloalkyl,
and unsubstituted or substituted heterocycloalkyl; R17 is selected from the
group
consisting of unsubstituted or substituted alkyl, unsubstrtuted or substituted

cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or
substituted
heteroaryl,-C(0)R18,
-C(O)OR18, and -S(O)2R20; wherein R18, R19 and R20 are independently selected
from
the group consisting of unsubstituted or substituted alkyl, and unsubstituted
or
substituted cycloalkyl;
wherein R16 and R17 combine with N to which they are attached to form
unsubstituted or substituted 3- to 12- membered heterocyclic, or unsubstituted
or
substituted 5- to 12- membered heteroaryl; and
wherein Z1 and Z2 can join together to form a bond or combine with atoms to
which they are attached to form unsubstituted or substituted C6-12
cycloalkenyl,
unsubstituted or substituted 5- to 12- membered heterocyclic, unsubstituted or

substituted C6-12 aryl, or unsubstituted or substituted 5- to 12- membered
heteroaryl.
25. The compound of claim 24, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein A is N.
26. The compound of claim 24, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein A is selected from the group consisting of CH, CF and
CCI
27. The compound of claim 24, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein Z1, Z2 and Z3 are H.
28. The compound of claim 24, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein Z1 and Z3 are H, Z2 is -CH2NR16R17.

- 88 -
29. The compound of claim 24, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein Z1 and Z2 join together to form a bond.
30. The compound of claim 24, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein 3 or less than 3 of X1, X2, X3, X4, and X5 are
halogen.
31. The compound of claim 24, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein X1 is F.
32. The compound of claim 24, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein X2, X3, and X4 are hydrogen.
33. The compound of claim 24, a pharmaceutically acceptable salt, a
solvate, or a
hydrate thereof, wherein X5 is selected from the group consisting of H, F and
Cl.
34. A pharmaceutical composition comprising the compound of claim 1 or 2,
and
a pharmaceutically acceptable carrier.
35. Use of an effective amount of the compound of claim 1 or 2, or the
pharmaceutically acceptable salt thereof, to modulate protein tyrosine kinase
activity
in a cell.
36. Use of the compound of claim 1 or claim 2, or the pharmaceutically
acceptable salt thereof, to treat a condition or a disease mediated by protein
tyrosine
kinase in a subject.
37. The use of claim 36, wherein the condition or the disease is cancer or
autoimmune diseases.

- 89 -
38. The use of claim 37, wherein the cancer is B-cell malignancies,
selected from
the group consisting of chronic lymphocytic leukemia (CLL), mantle cell
lymphoma
(MCL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM),
follicular
lymphoma (FL), marginal zone lymphoma, and waldenstrom's macroglobulinemia
(WM).
39. A compound, a tautomer, a pharmaceutically acceptable salt, a solvate,
or a
hydrate thereof, wherein the compound is selected from the group consisting
of:
Image

- 90 -
Image

- 91 -
Image

- 92 -
Image

- 93 -
Image

- 94 -
Image

- 95 -
Image

- 96 -
Image

- 97 -
Image

- 98 -
Image

- 99 -
Image

- 100 -
Image

- 101 -
Image

- 102 -
Image
40. The compound
of claim 39, a tautomer, a pharmaceutically acceptable salt, a
solvate, or a hydrate thereof, wherein the compound is
Image

- 103 -
41. The compound
of claim 39, a tautomer, a pharmaceutically acceptable salt, a
solvate, or a hydrate thereof, wherein the compound is
Image

Description

CA 02953798 2016-12-23
WO 2016/007185
PCT/US2014/061393
- 1 -
AMINOPYRIDAZINONE COMPOUNDS AS PROTEIN
KINASE INHIBITORS
TECHNICAL FIELD
[0001] The present invention describes a series of new compounds that
display
potent inhibition against Bruton's tyrosine kinase and, therefore, may provide
a potential
therapeutic approach to treating human cancers including B-cell lymphoma and
autoimmune diseases such as rheumatoid arthritis, systemic lupus
erythematosus, and
multiple sclerosis.
BACKGROUND
[0002] Bruton's tyrosine kinase (Btk) is a non-receptor cytoplasmic
tyrosine kinase
belonging to the Tec family of kinases, members of which also include Tec,
ltk, Txk, and
Bmx. Most of these kinases are predominantly expressed in hematopoietic cells
and
play important roles in relaying signal transductions from cell surface
receptors to direct
cell development, differentiation, and other functions (Berg JJ et al. Annual
Review of
Immunology, 2005; 23:549-600). Btk is critical for B cell development,
differentiation,
maturation, and signaling (Mohamed AJ et al. Immunological Reviews, 2009;
228:58-
73). Loss-of-function mutations of Btk cause X linked agammaglobulinemia (XLA)
in
humans and X linked immunodeficiency in mice (Thomas JD et al. Science 1993;
261:355-358). Patients with XLA have normal pre-B cell populations in their
bone
marrow but these cells fail to mature and enter the circulation. Therefore,
these patients
essentially have no circulating B cells and are incapable of producing
antibodies.
[0003] BTK plays pivotal roles in B cell proliferation and activation
mediated by B cell
receptor (BCR). Upon BCR activation, Btk is translocated to the plasma
membrane
where it is phosphorylated and subsequently initiates a cascade of signaling
events
including activation of phospholipase Cy2 (PLCy2) and eventually leading to
calcium
mobilization and transcriptional regulation involving nuclear factor kappa B
(NF KB)
(Mohamed AJ et al. Immunological Reviews 2009; 228:58-73). Because of the
indispensable roles in BCR signaling pathway, it is believed that the kinase
activity of
Btk is critical for development and maintenance of a wide variety of B cell
malignancies,
including chronic lymphocytic leukemia (CLL) and a number of non-Hodgkin's
lymphoma (NHL) subtypes, mantle cell lymphoma (MCL), and diffuse large B cell
lymphoma (DLBCL) (Ponader S. et al. Blood 2012, 119:1182-1189; Honigberg LA et
al.
SUBSTITUTE SHEET (RULE 26)

CA 02953798 2016-12-23
WO 2016/007185
PCMJS2014/061393
- 2 -
Proceedings of the National Academy of Sciences, 2010, 107:13075-13080). In
addition, the role of B cell in the pathogenesis of rheumatoid arthritis,
systemic lupus
erythematosus, multiple sclerosis, and other immune disorders has been
clinically
demonstrated (Edwards JC et al. The New England Journal of Medicine, 2004,
350:2572-2581; Favas C et al. Nature Review Rheumatology, 2009, 5:711-716;
Hauset
SL et at. The New England Journal of Medicine, 2008, 358:676-688). Therefore,
targeting Btk with small molecule inhibitors may provide therapeutic benefit
for the
treatment of B cell malignancies and autoimmune diseases.
SUMMARY
[0004] In one
aspect, compounds are of formula (I), or pharmaceutically acceptable
salts, solvates, hydrates, metabolites, or prodrugs thereof:
0-B
Ra
Rb RC
NH2
Rd
N \A
HN
0 L'y
wherein:
A is selected from the group consisting of CR1 and N; and wherein R1 is
selected
from the group consisting of hydrogen, halogen, and unsubstituted or
substituted alkyl;
Rb, R and Rd are independently selected from the group consisting of
hydrogen, halogen, hydroxyl, nitro, cyano, unsubstituted or substituted alkyl,
and
unsubstituted or substituted alkoxyl;
B is selected from the group consisting of hydrogen, unsubstituted or
substituted
alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted
heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or
substituted
heteroaryl;
L is unsubstituted or substituted alkyl, or absent; and
Y is selected from the group consisting of unsubstituted or substituted
cycloalkyl,
unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted
aryl, and
unsubstituted or substituted heteroaryl.
SUBSTITUTE SHEET (RULE 26)

- 2a -
[0004a] Accordingly, in one aspect of the present invention there is
provided a
compound of formula (I), tautomers, rotamers, geometric isomers,
diastereomers,
racemates, and enantiomers, a pharmaceutically acceptable salt, a solvate, or
a hydrate
thereof,
O-B
Ra
c
Rb R
NH2
Rd
NV HN A \
I
0
wherein A is selected from the group consisting of CR and N; and wherein R
is
selected from the group consisting of hydrogen, halogen, and unsubstituted or
substituted alkyl;
Ra, Rb, Rc and Rd are independently selected from the group consisting of
hydrogen, halogen, hydroxyl, nitro, cyano, unsubstituted or substituted alkyl,
and
unsubstituted or substituted alkoxyl;
B is selected from the group consisting of hydrogen, unsubstituted or
substituted
alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted
heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or
substituted
heteroaryl;
L is unsubstituted or substituted alkylene, or absent; and
Y is selected from the group consisting of unsubstituted or substituted
cycloalkyl,
unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted
aryl, and
unsubstituted or substituted heteroaryl.
CA 2953798 2018-10-22

,
-2b -
[0004b] According to another aspect of the present invention
there is provided a
pharmaceutical composition comprising the compound described herein, and a
pharmaceutically acceptable carrier.
[0004c] According to another aspect of the present invention
there is provided a
use of an effective amount of the compound described herein, or the
pharmaceutically
acceptable salt thereof, to modulate protein tyrosine kinase activity in a
cell.
[0004d] According to another aspect of the present invention
there is provided a
use of the compound described herein, or the pharmaceutically acceptable salt
thereof,
to treat a condition or a disease mediated by protein tyrosine kinase in a
subject.
[0004e] According to another aspect of the present invention
there is provided a
compound, a tautomer, a pharmaceutically acceptable salt, a solvate, or a
hydrate
thereof, wherein the compound is selected from the group consisting of:
o .
o fe o 4.
NH2 NH2 NH2
41'7 I N\
HN N FIN I N
oN---(---- oN----C--- Ny
0 .
NH2 NH2
NH2
1 1 HN
1 1
HN N HN
N N
o 0 6 0
LAN ,I. N N
0 ; 0 ; 0 =
,
_
1 CA 2953798 2018-10-22

i
- 2c -
o = o = o =
NH2
NH2 NH2
N

I \
N ' \
1 I I\V \
1 I HN N
HN N HN N
0 o
N N N
)7-----
- 0 = 0.----' =
0=
0 . 0 .
NH2
N I \
NH2 HIV N NH
Y' 1 \ 0 r I HN \
N HN N
0 -----CN--.\-
HN----- 0 \----N___C--
0 ; 0 ; 0 ;
0=
0 .
0 .
NH2
NH2
NH2 ON
HN N
, HL

HN
N
I\V \
1 I HNY I r\I o
0
0 F 0
____N---\r"----
't-\N---C"--- HN---C---
F 0
0 ; F ; 0 ;
1 CA 2953798 2018-10-22

I
-2d -
0 = 0-0
NH2 NH
I \
FIN
N HN N
O L / 0 / \NI\j)____
/ tN-1("7-NBoc
0 = 0 =
, ,
0= 0
0 .
NH2 NH2
NH2
I
HN HN
N N
FIN
o
N
/ o
o---/-11 oN-C 0
o'CN .
0 = 0 ;
, ,
. . .
0 0 0
NH2 NH2 NH2
1 1 1\V 1 \ IK I \
HN FIN HN
N N N
O a / 0 0
N thl-eCI oN.---e
0 ; 0 ; 0 ;
* . .
0 0 0
NH2 NH2 NH2
iv I N
HNy------N H
HNN I
N
O 0
ol--eCN 0 ::::::,/ N"

o = o = 0 =
' CA 2953798 2018-10-22

i
-2e -
. .
o o
NH2 NH2
1V
1 I
HN N ) HN N
P'
0
ö --,ry¨N
0 )
/ o----r1
0 = 0 =
. .
O 0
NH2 NH2
N'
HIV ' HIV 1 N
P' N
l'
0 0
LNI-/s --N\ )
/
0 = 0 =
. .
O 0
NH2 NH2
Nv I \ tv I \
HN N )1 HN N
0
0 0
aNN\ aNr-/--N
0 ,= 0 =
,
. .
O 0
NH2 NH2
N'' , \
1 1
HIV 1
HN N N
0 0
L\N-0 t\I\NO
0 = 0 =
1 CA 2953798 2018-10-22

1
- 2f -
IP e
o 0
NH2 NH2
N'' 1 \
, 1
HN
N HN N
0
00
LN¨/---NON
0 = 0 =
, ,
0= 0 =
0
NH2
NH2 NH2
N' \
i'' 1 \ NV \
1 FIN N
HN
N HN
N 0
0
Ny's NI
0 = 0 = 0 I
=
0=
o= 0 .
NH2
NH2 NH2
FINN'. I \ NI' i \ N -.."
1 I \
N FIN HN
0 6
N
\ õõ N
0 --n
N 0
NI----/ N---/
d--.1Th 0
/ = \ = \ =
1 CA 2953798 2018-10-22

i
-2g -
0 = 0 =
0 .
NH2 NH2
N' NH2
HN HNN
N NV \
1 1
0 0 a HN
N
N\
F--t\N ---.Cr-
0
N--
/ = 0 = 0 =
0= 0=
0 = NH2
NH2
N'
NI"' \ I I

FIN \
N NH2 HN
N
N ' 6
0
o
HN
N/ N / /
HN-In/-
N\ HN---C-/---
N\
0 = 0 = 0
=
. F
NH2 NH2 NH2
I\V \
1 NI
I I \
I 1
HN I N HN
N HN
N
0 LN _;15p.
0 0
N_,\C--------/--N\./ oN-{------
F 0 = 0 = 0 ;
1 CA 2953798 2018-10-22

1
-2h -
F F F
0= 0 = 0
F
NH2 NH2 NH2
N." 1 \ N-' \
HIV ' HN HIV
N N N
0
L
I\I-{-/--N
N \ 0
LN--(-----
=
0 ; 0 , 0 ;
F
0
F
NH2 NH2
N'' \ IV- \
1 1
HN N HN N
0 0 ---N(
0 0
oN-C----
= = ,
,
0 . F
F F
NH2 NH2 NH2
N

I \ NI-- 1 \ r I \
WV ' N HN N
0 0
0 oN..õIry---N(
0 0 0
oN---(----
= = ;
,
,
CI . CI
0 . 0 0=
CI
NH2 NH2 NH
N-
Iµ
\
I r I \ V 1 \
HN I N HN N 41 ' N
0
okl---e--- 0
LN/--. NI\ 0
0 0 0
ol-r---
= = =
,
,
,
1 CA 2953798 2018-10-22

1
- 21 -
o = / o .
oi 13 * o
Ci ci CI
NH2 NH2 NH2
'iv I \ N-- ' \
1 1K I \
HN N HNI N HN N
0 0 /
N
LN-1r/--- N
N \
0 = 0 = 0 =
,
CI CI
CI
0= 0= / 0
0
CI
NH2 NH2 NH2
N'' , \
HN I
HN I
HN N N N
O 0 / 0
LW-C.-- or--/--N\ LN---C---
0 ; 0 =
, 0 =
,
. CI
/ 0 0 = 0 .
0 CI F F
NH2 NH2 NH2
\ N-- 1 \ N'' 1 \
HN I HN I
HN I N N N
O LN..r.õ,y--N\/ 0
oN---C-----
0 = 0 ; 0 =
,
,
CI
0 * 0 = 0
F
NH2 NH2 NH2
F F
1 1
HN N HN (N HN N
O 0 LN __ry-hi\ 0
LN-C--- LW-1r--
0 ; 0 =
, 0 ;
I CA 2953798 2018-10-22

1
- 2] -
Cl
0 = 0 = 0 =
F
NH2 NH2 NH2
INVI 1 \
I I \ CI I \ F
HN N HN N HN N
0
LW-1r-- 0
LN-C----
0 = 0 ; 0 ;
,
F
0 = 0 .
0
F
NH2 F
NH2 NH2
N'' 1 \ 1 1 ' CI
41 ' N HN N N-- , \
1 1
HN N
0 LN _/ , 0
LN-C----.- ; 0
LN-CN .
0 - 0
0 . 0 = 0=
F
F F
NH2 NH2 NH
1 1 s CI N'7 , \
1 1
HII I N HN N HN N
0 o0 0
-CN . o---CN . LN-CN .
0=
0= 0--
NH2
CI
N--- \
NH2 NH2 1
HN N
0
0
HI1 I N HNI I N
=
40 0)....._./ 0 . 0
HN--.(----
N N
H ,= H = 0 ;
,
'
1 CA 2953798 2018-10-22

i
- 2k -
F
F
0
0 . 0 .
F F
NH2
NH2 NH2
N-' \ N'' 1 \ HIV N
HIV N HNI I N N \ 0
0 0 --..
oN%
N)\---" N
H , = , H = 0
=
,
CI
= 46
0 0 0
F F CI
NH2 NH2 NH2
I\V
HIV N HIV ' N HNI I N
0 0 0
or_...,_--_-- oN,
0 = 0 = 0 ,=
* 4. . F
0 0 0
F
NH2 NH2 NH2
1 1 ly \
HN N HN N HN 1 N
0 0 0
Me0I-oN
oNly k
r--- NN
0 = 0 ; 0 =
1 CA 2953798 2018-10-22

i
- 21 -
. F
. F
= 0
0 F 0
NH2
NH2 NH2 Y' 1 \
HN
I\V \ NV- 1 \ N
1
FIN I m
HN N '7.
0
0 ,i3N. 0 //
HN
H \ = 0 = 0 ;
0
0
NH2 NH2 NH2
NH2
N 1 \ N'' , \
I
1 1
HN N HN N HN N N

1 \
HN
0 a 0 0 o N
0
41/ HN---e---- FIN ---.C: oN
=1---\-.NN
0 ; 0 ; 0 ; 0 ;
F
0
0= 0=
F
NH2
NH2 NH2
N 1 \
NV 1 \
I \ HN II NN
FIN I N HN N
0 oN-CN
0
0 L\N-C-----
oN,
CN = . 0 ;
,
, CA 2953798 2018-10-22

1
-2m -
F
4, 0 .
0 * 0
NH2 NH
NH2
N'' \ NV 1 \
NV 1 \ I I ,N HNN I I N
I I N HN N
HN N
0 0
OLNoy-f,' ----1N
-r----
0 ; 0 =
, 0 =
,
F
:0
F
F F
NH2
NH2 NH2
NV \
FIN N'N 1_11V I \
N N HN \
N
O ,
0 0
oN %-. CN .--e-'
0 = 0 ; 0 ;
'
. F
F F
0
0 4, 0 F
N\>
F
NH2
NH2 NH2
I
F N
NV \
1 I NV \
1 N
HN N HNI N
O 0 LW/ il
0 oN
t\N--\r"-/
0 = 0 ;and 0 .
,
i CA 2953798 2018-10-22

CA 02953798 2016-12-23
WO 2016/007185 PCMJS2014/061393
- 3 -
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] Fig. 1 illustrates effect of Btk inhibitors on tumor growth in TMD-8
xenograft
model.
[0006] Fig. 2 illustrates effect of Btk inhibitors on tumor growth in TMD-8
xenograft
model (final tumor weight).
DETAILED DESCRIPTION
[0007] This disclosure relates generally to compounds that modulate protein
tyrosine
kinase activity, methods of synthesizing, and using such compounds in
therapeutic
methods.
Definitions
[0008] Any terms in the present application, unless specifically defined,
will take the
ordinary meanings as understood by a person of ordinary skill in the art.
[0009] As used herein, the singular forms "a", "an", and "the" include
plural reference
unless the context clearly dictates otherwise.
[0010] Unless stated otherwise, all aryl, cycloalkyl, heteroaryl, and
heterocyclyl
groups of the present disclosure may be substituted as described in each of
their
respective definitions. For example, the aryl part of an arylalkyl group, such
as benzyl,
may be substituted as described in the definition of the term "aryl."
[0011] The term "alkoxy," as used herein, refers to a C1-C10, preferably C1-
C6, alkyl
group attached to the parent molecular moiety through an oxygen atom.
Representative
examples of alkoxy group include, but are not limited to, methoxy (CH30-),
ethoxy
(CH3CH20-), and t-butoxy ((CH3)3C0-).
[0012] The term "alkyl," as used herein, refers to a group derived from a
straight or
branched chain saturated hydrocarbon by removal of a hydrogen from one of the
saturated carbons. The alkyl group preferably contains from one to ten carbon
atoms,
more preferably one to six carbon atoms. Representative examples of alkyl
group
include, but are not limited to, methyl, ethyl, isopropyl, and tert-butyl.
[0013] The term "aryl," as used herein, refers to a group derived from a C6-
C12,
preferably C6-C10, aromatic carbocycle by removal of a hydrogen atom from an
aromatic
ring. The aryl group can be monocyclic, bicyclic or polycyclic. Preferred
examples of
aryl groups include phenyl and naphthyl.
[0014] The term "cyano," as used herein, refers to -CN.
SUBSTITUTE SHEET (RULE 26)

CA 02953798 2016-12-23
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PCMJS2014/061393
- 4 -
[0015] The term "cycloalkyl," as used herein, refers to a group derived
from a
monocyclic saturated carbocycle, having preferably three to eight, more
preferably three
to six, carbon atoms, by removal of a hydrogen atom from the saturated
carbocycle.
Representative examples of cycloalkyl groups include, but are not limited to,
cyclopropyl,
cyclopentyl, and cyclohexyl. When a cycloalkyl group contains one or more
double
bond(s) in the ring, yet not aromatic, it forms a "cycloalkenyl" group.
[0016] The terms "halo" and "halogen," as used herein, refer to F, CI, Br,
or I.
[0017] The term "haloalkoxy," as used herein, refers to a C1-C6, preferably
C1-C4,
haloalkyl group attached to the parent molecular moiety through an oxygen
atom.
[0018] The term "haloalkyl," as used herein, refers to a Craw, preferably
C1-C6,
more preferably C1-C4, alkyl group substituted by at least one halogen atom.
The
haloalkyl group can be an alkyl group of which all hydrogen atoms are
substituted by
halogens. Representative examples of haloalkyl include, but are not limited
to,
trifluoromethyl (CF3-), 1-chloroethyl (CICH2CH2-), and 2,2,2-trifluoroethyl
(CF3CH2-).
[0019] The term "heteroaryl," as used herein, refers to a 5- to 10-
membered,
monocyclic or bicyclic aromatic group comprising one or more, preferably one
to three,
heteroatoms independently selected from nitrogen, oxygen, and sulfur in the
aromatic
ring(s). As is well known to those skilled in the art, heteroaryl rings have
less aromatic
character than their all-carbon counterparts. Thus, for the purposes of the
invention, a
heteroaryl group need only have some degree of aromatic character.
Illustrative
examples of heteroaryl groups include, but are not limited to, pyridyl,
pyridazinyl,
pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyrimidinyl,
furyl, thienyl,
isoxazolyl, thiazolyl, isoxazolyl, oxazolyl, indolyl, quinolinyl,
isoquinolinyl, benzisoxazolyl,
benzothiazolyl, and benzothienyl.
[0020] The term "heterocyclyl," as used herein, refers to a 3- to 10-
membered
monocyclic or bicyclic nonaromatic group comprising one or more, preferably
one to
three, heteroatoms independently selected from nitrogen, oxygen, and sulfur in
the
nonaromatic ring(s). The heterocyclyl groups of the present disclosure can be
attached
to the parent molecular moiety through a carbon atom or a nitrogen atom in the
group. A
heterocylcyl group can be saturated or unsaturated, for example, containing
one or
more double bond(s) in the ring. Examples of heterocyclyl groups include, but
are not
limited to, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrrolidinyl,
tetrahydrofuryl,
thiomorpholinyl, and indolinyl, or the like.
[0021] The terms "hydroxy" or "hydroxyl," as used herein, refers to -OH.
SUBSTITUTE SHEET (RULE 26)

CA 02953798 2016-12-23
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PCMJS2014/061393
- 5 -
[0022] The term "nitro," as used herein, refers to -NO2.
[0023] The term "oxo," as used herein, refers to "=0".
[0024] When any group, for example, alkyl, alkenyl, "cycloalkyl," "aryl,"
"heterocyclyl,"
or "heteroaryl", is said to be "optionally substituted," unless specifically
defined, it means
that the group is or is not substituted by from one to five, preferably one to
three,
substituents independently selected from halogen, alkyl, alkoxy, haloalkyl,
haloalkoxy,
hydroxy, oxo, acyl, cyano, nitro, and amino group, or the like, provided that
such
substitution would not violate the conventional bonding principles known to a
person of
ordinary skill in the art. When the phrase "optionally substituted" is used
before a list of
groups, it means that each one of the groups listed may be optionally
substituted.
[0025] The compounds of the present disclosure can exist as
pharmaceutically
acceptable salts or solvates. The term "pharmaceutically acceptable salt," as
used
herein, means any non-toxic salt that, upon administration to a recipient, is
capable of
providing the compounds or the prodrugs of a compound of this invention. The
salts can
be prepared during the final isolation and purification of the compounds or
separately by
reacting a suitable nitrogen atom with a suitable acid. Acids commonly
employed to form
pharmaceutically acceptable salts include inorganic acids such as hydrochloric
acid,
hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen
bisulfide as
well as organic acids, such as para-toluenesulfonic acid, salicylic acid,
tartaric acid,
bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid,
gluconic acid,
glucuronic acid, formic acid, glutamic acid, methanesulfonic acid,
ethanesulfonic acid,
benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid,
carbonic
acid, succinic acid, citric acid, benzoic acid, acetic acid acid, and related
inorganic and
organic acids.
[0026] Basic addition salts can be prepared during the final isolation and
purification
of the compounds by reacting a carboxy group with a suitable base such as the
hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an
organic
primary, secondary, or tertiary amine. The cations of pharmaceutically
acceptable salts
include, but are not limited to, lithium, sodium, potassium, calcium,
magnesium, and
aluminum, as well as nontoxic quaternary amine cations such as ammonium,
tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,
trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine,
pyridine, N,N-
dimethylaniline, N-methylpiperidine, and N-methylmorpholine.
[0027] The term "solvate," as used herein, means a physical association of
a
SUBSTITUTE SHEET (RULE 26)

CA 02953798 2016-12-23
WO 2016/007185
PCT/1JS2014/061393
- 6 -
compound of this invention with one or more, preferably one to three, solvent
molecules,
whether organic or inorganic. This physical association includes hydrogen
bonding. In
certain instances the solvate will be capable of isolation, for example when
one or more,
preferably one to three, solvent molecules are incorporated in the crystal
lattice of the
crystalline solid. Exemplary solvates include, but are not limited to,
hydrates,
ethanolates, methanolates, and isopropanolates. Methods of solvation are
generally
known in the art.
[0028] The term "therapeutically effective amount," as used herein, refers
to the total
amount of each active component that is sufficient to show a meaningful
patient benefit,
e.g., a sustained reduction in viral load. When applied to an individual
active ingredient,
administered alone, the term refers to that ingredient alone. When applied to
a
combination, the term refers to combined amounts of the active ingredients
that result in
the therapeutic effect, whether administered in combination, serially, or
simultaneously.
[0029] The term "pharmaceutically acceptable," as used herein, refers to
those
compounds, materials, compositions, and/or dosage forms which are, within the
scope
of sound medical judgment, suitable for use in contact with the tissues of
patients
without excessive toxicity, irritation, allergic response, or other problem or
complication
commensurate with a reasonable benefit/risk ratio, and are effective for their
intended
use.
[0030] The term "patient" includes both human and other mammals.
[0031] The term "treating" refers to: (i) preventing a disease, disorder or
condition
from occurring in a patient that may be predisposed to the disease, disorder,
and/or
condition but has not yet been diagnosed as having it; (ii) inhibiting the
disease, disorder,
or condition, i.e., arresting its development; and (iii) relieving the
disease, disorder, or
condition, i.e., causing regression of the disease, disorder, and/or
condition.
[0032] In one embodiment, compounds are of formula (I), or pharmaceutically

acceptable salts, solvates, hydrates, metabolites, or prodrugs thereof:
SUBSTITUTE SHEET (RULE 26)

CA 02953798 2016-12-23
WO 2016/007185
PCMJS2014/061393
- 7 -
0¨B
Ra
Rb Rc
NH2
Rd
N \
I I A
HN
0 y
wherein:
A is selected from the group consisting of CR1 and N; and wherein R1 is
selected
from the group consisting of hydrogen, halogen, and unsubstituted or
substituted alkyl;
R5, Rb, RC and Rd are independently selected from the group consisting of
hydrogen, halogen, hydroxyl, nitro, cyano, unsubstituted or substituted alkyl,
and
unsubstituted or substituted alkoxyl;
B is selected from the group consisting of hydrogen, unsubstituted or
substituted
alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted
heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or
substituted
heteroaryl;
L is unsubstituted or substituted alkyl, or absent; and
Y is selected from the group consisting of unsubstituted or substituted
cycloalkyl,
unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted
aryl, and
unsubstituted or substituted heteroaryl.
[0033] In some embodiments, A is selected from the group consisting CH, OF,
CCI
and N.
[0034] In some embodiments, at least one of Ra, Rb, RC and Rd is selected
from the
group consisting of hydrogen, F, Cl, and methoxyl. In some embodiments, Ra,
Rb,
RG
and Rd are hydrogen. In some embodiments, Ra is F, Cl, or methoxyl. In some
embodiments, Rd is F, Cl, or methoxyl.
[0035] In some embodiments, B is unsubstituted or substituted C1-06 alkylln
some
embodiments, B is unsubstituted or substituted aryl. In some embodiments, B is

unsubstituted or substituted phenyl. In some embodiments, B is phenyl. In some

embodiments, B is phenyl substituted with at least one member selected from
the group
consisting of halogen, cyano, nitro, hydroxyl, unsubstituted or substituted
alkyl,
unsubstituted or substituted alkoxy, -NR1R2, -C(0)R3, -C(0)0R4,
SUBSTITUTE SHEET (RULE 26)

CA 02953798 2016-12-23
WO 2016/007185 PCMJS2014/061393
- 8 -
-C(0)NHR5, and -S(0)2R6. R1 and R2 are independently selected from the group
consisting of hydrogen, unsubstituted or substituted alkyl, -C(0)R7, -C(0)0R8,
-C(0)NHR9, -S(0)2R18; and wherein R3, R4, R5, R6, R7,
K R9, and R1 are independently
selected from the group consisting of unsubstituted or substituted alkyl,
unsubstituted or
substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl,
unsubstituted or
substituted aryl, and unsubstituted or substituted heteroaryl.
[0036] In some embodiments, B is phenyl substituted with at least one
member
selected from the group consisting of F, CI, and methoxyl. In some
embodiments, B is
phenyl substituted with two F. In some embodiments, B is phenyl substituted
with two Cl.
In some embodiments, B is phenyl substituted with one Cl and one methoxyl.
[0037] In some embodiments, L is absent. In some embodiments, L is
methylene.
[0038] In some embodiments, Y is selected from the group consisting of
unsubstituted or substituted piperidinyl, unsubstituted or substituted phenyl,
unsubstituted or substituted bicyclo[3.2.1]octanyl, unsubstituted or
substituted azetidinyl,
and unsubstituted or substituted pyrrolidinyl. In some embodiments, Y is
substituted with
at least one member selected from the group consisting of halogen, -CN, -
C(0)R11,
)- _
-NHC(0 K12, S(0)2R13, and -NHS(0)2R14; and wherein R11, R12, 1- -13,
and R14 are
independently selected from the group consisting of unsubstituted or
substituted alkyl,
unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkenyl,

unsubstituted or substituted cycloalkenyl, and unsubstituted or substituted
alkynyl.
[0039] In some embodiments, Y is substituted with at least one member
selected
from the group consisting of F, CN,-C(0)CH=CH2, -C(0)CH=CHCH2N(CH3)2,
-NHC(0)CH=CH2, -NHC(0)CH=CHCH2N(CH3)2, -C(0)CH=CHCH2N(CH3)(COOC(CH3)3;
-C(0)CH=CHCH2NH(CH3),
ci
-C(0)CH2CH3, -C(0)CH2CH2CH3, I
lEgi
-C(0)CH2CNõ 0 , 0 , 0 , 0
N\ 1\1\
SUBSTITUTE SHEET (RULE 26)

CA 02953798 2016-12-23
WO 2016/007185
PCMJS2014/061393
- 9 -
N N0 NN
0 ---
0
0 1
, and ffIr
[0040] In some
embodiments, the compound has both S-form and R-form. In some
embodiments, the compound has more R-form than S-form. In some embodiments,
the
compound has more S-form than R-form.
[0041] In some embodiments, the compound has a structure of formula (II):
X2
0X1
= X3
X
\ X5 4
NH2
N' \
I I A
HN
)
q
where Ra, A, and L are defined as in formula (I);
X1, X2, X3, X4, and X5 are independently selected from the group consisting of

hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted alkyl,

unsubstituted or substituted alkoxy, -NR1R2, -C(0)R3, -C(0)0R4, -C(0)NHR5, and

-S(0)2R6;
wherein R1 and R2 are independently selected from the group consisting of
hydrogen, unsubstituted or substituted alkyl, -C(0)R7, -C(0)0R8, -C(0)NHR9, -
S(0)2R16;
and wherein R3, R4, R5, R6, R7, R8, Rg, and R1 are independently selected
from the
group consisting of unsubstituted or substituted alkyl, unsubstituted or
substituted
cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or
substituted
aryl, and unsubstituted or substituted heteroaryl;
W is selected from the group consisting of halogen, hydroxyl, unsubstituted or

substituted alkyl, and unsubstituted or substituted alkoxyl; wherein two W may
combine
SUBSTITUTE SHEET (RULE 26)

CA 02953798 2016-12-23
WO 2016/007185
PCMJS2014/061393
- 10 -
with an atom or atoms to which they are attached to form unsubstituted or
substituted
03_12 cycloalkyl, unsubstituted or substituted 3- to 12- membered
heterocyclic,
unsubstituted or substituted C6-12 aryl, or unsubstituted or substituted 5- to
12-
membered heteroaryl;
m = 0, 1,2, or 3;
p = 1,2, or 3;
q = 0, 1, or 2;
s = 0, 1,2, or 3; and
Z is selected from the group consisting of -NHC(0)R12, and
-NHS(0)2R14; and wherein R12, and R14 are independently selected from the
group
consisting of unsubstituted or substituted alkyl, unsubstituted or substituted
cycloalkyl,
unsubstituted or substituted alkenyl, unsubstituted or substituted
cycloalkenyl, and
unsubstituted or substituted alkynyl.
[0042] In some embodiments, A is N, CH, CF or CCI. In some embodiments, L
is
absent or -CH2-. In some embodiments, p and q are independently 1 or 2. In
some
embodiments, s is 1 or 2.
[0043] In some embodiments, Z is selected from the group consisting of -
NHC(0)CH=CH2, -NHC(0)CH=CHCH2N(CF13)2,
0
)5S.
and
[0044] In some embodiments, the compound has a structure of formula (III):
X2
X1
X3
0
X4
\ X5
NH2
N

HNN'A \
I
0 1- WS
-( q
Ill Z
P N
where Ra, A, L, X1, X2, X3, X4, X5, W, p, q, s and m are defined as above.
SUBSTITUTE SHEET (RULE 26)

CA 02953798 2016-12-23
WO 2016/007185
PCMJS2014/061393
- 11 -
Z is selected from -CN, -C(0)R11
and -S(0)2R13, and wherein R11 and R13 are independently selected from the
group
consisting of unsubstituted or substituted alkyl, unsubstituted or substituted
cycloalkyl,
unsubstituted or substituted alkenyl, unsubstituted or substituted
cycloalkenyl, and
unsubstituted or substituted alkynyl.
[0045] In some embodiments, Z is selected from the group consisting of CN,-
C(0)CH=CH2, -C(0)CH=CHCH2N(CH3)2,
-C(0)CH=CHCH2N(CH3)(000C(CH3)3; -C(0)CH=CHCH2NH(CH3),
o
-C(0)CH2CH3, -C(0)CH2CH2CH3, 0 0
=N\
-C(0)CH2CNõ 0 , 0 , 0 , 0
1 1
0
and .jyrrs
[0046] In some embodiments, the compound has formula (IV):
x2
0xl
* x3
x4
\ x5
NH2
N
I I
IV
SUBSTITUTE SHEET (RULE 26)

CA 02953798 2016-12-23
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PCMJS2014/061393
- 12 -
where R5, X1, X2, X3, X4, X5, W, Z, and m are defined as above.
[0047] In some embodiments, Z is selected from the group consisting of -
NHC(0)R12
and -NHS(0)2R14.
[0048] In some embodiments, the compound has formula (V):
x2
0x1,

x3
x4
\ x5
NH2
N \A
.7 Z1
P
V 0 Z3
where Ra, A, X1, X2, X3, X4, X5, W, s, and m are defined as above;
Z1 is selected from the group consisting of hydrogen, halogen, cyano, and
unsubstituted or substituted alkyl; and
Z2 and Z3 are independently selected from the group consisting of hydrogen,
unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl,
unsubstituted
or substituted heterocycloalkyl, -0H20R15, and -CH2NR16R17;
R15 and R16 are independently selected from the group consisting of hydrogen,
unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl,
and
unsubstituted or substituted heterocycloalkyl; R17 is selected from the group
consisting
of unsubstituted or substituted alkyl, unsubstituted or substituted
cycloalkyl,
unsubstituted or substituted aryl, and unsubstituted or substituted
heteroaryl, -C(0)R18,
-C(0)0R19, and -S(0)2R20; wherein R18, R19 and R2 are independently selected
from the
group consisting of unsubstituted or substituted alkyl, and unsubstituted or
substituted
cycloalkyl;
R16 and R17 combine with N to which they are attached to form unsubstituted or

substituted 3-to 12- membered heterocyclic, or unsubstituted or substituted 5-
to 12-
membered heteroaryl; and
Z1 and Z2 can join together to form a bond or combine with atoms to which they

are attached to form unsubstituted or substituted C5_12 cycloalkenyl,
unsubstituted or
substituted 5- to 12- membered heterocyclic, unsubstituted or substituted C6-
12 aryl, or
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unsubstituted or substituted 5-to 12- membered heteroaryl.
[0049] In some embodiments, A is selected from the group consisting of CH,
CF and
CCI.
[0050] In some embodiments, Z1, Z and Z3 are H. In some embodiments, Z1 and
Z2
join together to form a bond . In some embodiments, Z1 and Z3 are hydrogen, Z2
is -
CH2NR16R17.
[0051] In some embodiments, 301 less than 3 of X1, X2, X3, X4, and X5 are
halogen.
In some embodiments, X1 is F. In some embodiments, X2, X3, and X4 are
hydrogen. In
some embodiments, X5 is selected from the group consisting of H, F and Cl.
[0052] Although all of the above structure formulas were drawn as certain
isomers for
convenience, the present invention may include all isomers, such as,
tautomers,
rotamers, geometric isomers, diastereomers, racemates, and enantiomers.
[0053] Tautomers are constitutional isomers of organic compounds that
readily
interconvert by a chemical reaction called tautomerization. This reaction
commonly
results in the formal migration of a hydrogen atom or proton, accompanied by a
switch
of a single bond and adjacent double bond. A couple of the common tautomeric
pairs
are: ketone - enol, lactam - lactim. An example of lactam - lactim equilibria
is between A
and B as shown below.
NH2 NH2
\A -5(N----N
HN
0 OH
A
[0054] All the compounds in the present disclosure can be drawn as either
form A or
form B. All tautomeric forms are included in the scope of the invention. The
naming of
the compounds does not exclude any tautomers.
[0055] Pharmaceutical compositions or formulations of the present invention
include
those suitable for oral, nasal, topical (including buccal and sublingual),
rectal, vaginal
and/or parenteral administration. Regardless of the route of administration
selected, the
active ingredient(s) are formulated into pharmaceutically acceptable dosage
forms by
methods known to those of skill in the art.
[0056] The amount of the active ingredient(s) which will be combined with a
carrier
material to produce a single dosage form will vary depending upon the host
being
treated, the particular mode of administration and all of the other factors
described
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above. The amount of the active ingredient(s) which will be combined with a
carrier
material to produce a single dosage form will generally be that amount of the
active
ingredient(s) which is the lowest dose effective to produce a therapeutic
effect.
[0057] Methods of preparing pharmaceutical formulations or compositions
include
the step of bringing the active ingredient(s) into association with the
carrier and,
optionally, one or more accessory ingredients. In general, the formulations
are prepared
by uniformly mixing the active ingredient(s) into liquid carriers, or finely
divided solid
carriers, or both, and then, if necessary, shaping the product.
[0058] Exemplary, non-limiting examples of formulations of the disclosure
suitable for
oral administration may be in the form of capsules, cachets, pills, tablets,
lozenges
(using a flavored basis, usually sucrose and acacia or tragacanth), powders,
granules,
or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an
oil-in-
water or water-in-oil liquid emulsion, or as an elixir or syrup, or as
pastilles (using an
inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as
mouth
washes and the like, each containing a predetermined amount of the active
ingredient(s).
[0059] In solid dosage forms of the invention for oral administration
(capsules, tablets,
pills, dragees, powders, granules and the like), the prodrug(s), active
ingredient(s) (in
their micronized form) is/are mixed with one or more pharmaceutically-
acceptable
carriers known to those of skill in the art. Examples of suitable aqueous and
nonaqueous carriers which may be employed in the pharmaceutical compositions
of the
invention include water, ethanol, polyols (such as glycerol, propylene glycol,

polyethylene glycol, and the like), and suitable mixtures thereof. Proper
fluidity can be
maintained, for example, by the use of coating materials, such as lecithin, by
the
maintenance of the required particle size, and by the use of surfactants.
[0060] These compositions may also contain adjuvants such as wetting
agents,
emulsifying agents and dispersing agents. It may also be desirable to include
isotonic
agents, such as sugars, sodium chloride, and the like in the compositions. In
addition,
prolonged absorption of the injectable pharmaceutical form may be brought
about by the
inclusion of agents which delay absorption such as aluminum monostearate and
gelatin.
[0061] In some cases, in order to prolong the effect of the active
ingredient(s), it is
desirable to slow the absorption of the drug from subcutaneous or
intramuscular
injection. This may be accomplished by the use of a liquid suspension of
crystalline or
amorphous material having poor water solubility. The rate of absorption of the
active
ingredient(s) then depends upon its/their rate of dissolution which, in turn,
may depend
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upon crystal size and crystalline form.
[0062] The formulations may be presented in unit-dose or multi-dose sealed
containers, for example, ampoules and vials, and may be stored in a
lyophilized
condition requiring only the addition of the sterile liquid carrier, for
example water for
injection, immediately prior to use. Extemporaneous injection solutions and
suspensions
maybe prepared from sterile powders, granules and tablets of the type
described above.
[0063] The present disclosure includes a method of modulating protein
tyrosine
kinase activity, comprising contacting a cell with an effective amount of any
compound
of formulae (I)-(V) or the pharmaceutically acceptable salt thereof.
[0064] The present disclosure includes a method of treating a condition or
a disease
mediated by protein tyrosine kinase, comprising administering to a subject a
therapeutically effective amount of any compound of formulae (I)-(V), or the
pharmaceutically acceptable salt thereof. In some embodiments, the condition
or the
disease is cancer or autoimmune diseases. In some embodiments, the cancer is B-
cell
malignancies. In some embodiments, the cancer is chronic lymphocytic leukemia
(CLL),
mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), multiple
myeloma
(MM), follicular lymphoma (FL), armginal zone lymphoma and waldenstrom's
macroglobulinemia (WM). In some embodiments, the autoimmune disease is
rheumatoid arthritis. In some embodiments, the autoimmune disease is systemic
lupus
erythematosus.
Synthetic Methods
Abbreviations
[0065] Abbreviations which have been used in the descriptions of the
schemes and
the examples that follow are:
[0066] Cy for cyclohexane
[0067] DAST for diethylaminosulfur trifluoride;
[0068] DCM for dichloromethane;
[0069] DIEA or DIPEA for diisopropyl ethylamine;
[0070] DMAP for N,N-dimethylaminopyridine;
[0071] DME for ethylene glycol dimethyl ether;
[0072] DMF for N,N-dimethyl formamide;
[0073] DMSO for dimethylsulfoxide;
[0074] DPPA for diphenoxyphosphoryl azide;
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[0075] EDCI or EDC for 1-(3-diethylaminopropyI)-3-ethylcarbodiimide
hydrochloride;
[0076] ESI for electrospray ionization;
[0077] Et for ethyl;
[0078] Et0Ac for ethyl acetate;
[0079] g for gram(s);
[0080] h for hour(s);
[0081] HATU for 0-(7-Azabenzotriazole-1-y1)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate;
[0082] HBTU for 0-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-
phosphate;
[0083] HPLC for high-performance liquid chromatography;
[0084] mCPBA for 3-Chloroperbenzoic acid;
[0085] Me for methyl;
[0086] Me0H for methanol;
[0087] mg for milligram(s);
[0088] min for minute(s);
[0089] MS for mass spectrometry;
[0090] NBS for N-Bromosuccinimide;
[0091] NCS for N-Chlorosuccinimide;
[0092] NMR for nuclear magnetic resonance;
[0093] Pd(dppf)C12for [1,1'-
Bis(diphenylphosphino)ferrocene]dichloropalladium(II);
[0094] Pd2(dba)3 for Tris(dibenzylideneacetone)dipalladium(0);
[0095] PG for protecting groups;
[0096] Ph for phenyl;
[0097] PPh3 for triphenylphosphine;
[0098] rt for room temperature;
[0099] TEA for triethyl amine;
[00100] TFA for trifluoroacetic acid;
[00101] THF for tetrahydrofuran;
[00102] TLC for thin layer chromatography; and
[00103] tBOC or Boc for tert-butyloxy carbonyl.
[00104] The compounds and processes of the present invention will be better
understood in connection with the following synthetic schemes that illustrate
the
methods by which the compounds of the invention may be prepared. Other
reaction
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schemes could be readily devised by those skilled in the art.
Scheme 1
0 fit ()on
0 OH H2N ' HO 0 L---y I- "' Dr, NC
NC Br .(Ra)m
Et0 ¨ ,_
\ , \
1-2 i \> Br2
y
1 (R0)2B 1-5
__________________________________________________________ ...
NC \ / OEt EtO2C-'-.N ¨I'EtO2C-N
CN L.--PG L.....õ.pG Suzuki
1-1 1-3 1-4 '
(x)nQ-o /---\--
\ I o¨P--00,-, o 4t6 Nr,
/ \¨(Ra)m H2NNH2 NH2 ----(Ra)m
. _______________________________________ .
NC Et0H,reflux N' 1 \
¨* PG 1 \
HN,ir---N
Et020"---N, PG o L---y.
L----y
1-6 1-7 1-8
[00105] Triene 1-1 and amine 1-2 stirred in organic solvents (e.g. Et0Ac) at
elevated
temperature to afford pyrrole 1-3. Bromination with Br2 or other proper
reagents gave
bromide 1-4, which reacted with readily available bronic acid or bronic ester
1-5 under
Suzuki reaction conditions to give 1-6. Ester 1-6 and hydrazine refluxed in
Et0H gave
key intermediate 1-7. Deprotection and Z installation yielded 1-8.
Scheme 2
(X)
0-0
(H0)2B
NC..\\ Br2 NC Br
b
---NHPG NC Br / \
NH2 --------(Ra)rn
I ¨I. ....1.'-'sc __
EtO2C N ¨I. il I \
EtO2C 11 EtO2C"....' hi Cu(OAc)2,PY HN
Ir'N
2-1 2-2 2-3 ----' b1\1HPG 0 o
2-4 _.._-..
Z
[00106] Alternatively, pyrrole 2-1 without N substitute was prepared, followed
by
bromination to afford bromide 2-2. The aromatic ring was installed via copper
catalyzed
C-N cross-coupling reactions. The resulting intermediate 2-3 was transformed
to final
compound 2-4 via similar sequences illustrated in Scheme 1.
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Scheme 3
(X)õ
0-0
NC
Br /
Br2, Br
/ NH2
NaOH NC Mitsunobu
I \>
EtO,c

Et0...0 N EtO,C N N
11
0 ri L-Y,
PG
HN-
3-1 3-2 3-3 0
3-4
[00107] Pyrazole 3-1 reacted with Br2 under basic conditions gave bromide 3-2.
Y
group was installed via Mitsunobu reactions. 3-3 was converted to 3-4
following similar
sequences illustrated in Scheme 1.
EXAMPLES
[00108] The compounds and processes of the present invention will be better
understood in connection with the following examples, which are intended as an

illustration only and not limiting of the scope of the invention. Various
changes and
modifications to the disclosed embodiments will be apparent to those skilled
in the art
and such changes and modifications including, without limitation, relating to
the
chemical structures, substituents, derivatives, formulations and/or methods of
the
invention may be made without departing from the spirit of the invention and
the scope
of the appended claims.
[00109] Example 1. (R)-1-(1-acryloylpiperidin-3-y1)-4-amino-3-(4-
phenoxypheny1)-1H-
pyrrolo[2,3-d]pyridazin-7(6H)-one
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H2N
NC CN OH
aNBoc NC
la Et0Na, Et0H Ir-
0 + EtO2C,ry.CO 1c 2Et ' tE 02C N
EtO)YOEt 0 C to rt OH CN Et0Ac, reflux
0 A lb B ld aNBoc
0 .
Br 0
Br2, cH2c1 2 NC, j 40 If 40 B(OH)2
NC H2NNH2
0 C EtO2C N I \
Pd(dppf)C12, Na2CO3 N Et0H,reflux
C le NBoc dioxane, 80 C EtO2C
E
D aNBoc
1g
0 . 0 . 0 =
NH2
TFA, DCM N. , 0 HN NI" \
'
HN N HBTU, DIEA HN N
0
lh aNBoc F 0 1i aNH G
1 0
Step lA
[00110] To a solution of Et0Na (160 ml, solution of 21% in Et0H, 0.49 mmol) in
Et0H
(110 ml) in ice bath was added diethyl oxalate (64 ml, 0.47 mol). The mixture
was stirred
for 30 min. A solution of la (16 g, 0.15 mmol) in Et0H (30 ml) was added. The
resulting
mixture was stirred overnight at room temperature. After cooled in ice bath,
the
suspension was filtered. The solid was washed with small amount Et0H and then
dissolved in water (380 ml). The solution was acidified by HC1 to pH ¨4. Large
amount
solid appeared, filtered, washed with water, dried gave lb (11.9 g) as yellow
solid.
Step 1B
[00111] To a solution of lb (2.3 g, 7.5 mmol) in Et0Ac (120 ml) at 60 C was
added
dropwise a solution of lc (2.3 g, 11.4 mmol) in Et0Ac (32 ml). The mixture was
refluxed
for 4 h. After cooled to room temperature, the solvents were removed. The
residue was
purified by silica gel chromatography to afford light yellow oil Id (1.09 g).
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Step 1C
[00112] To a solution of Id (1.09 g) in DCM (200 ml) was added slowly a
solution of
Br2 (6.15g) in DCM (7 ml) over 30 min. The mixture was stirred for 30 min, and
then
quenched with a solution of 10% Na2S203 and saturated solution of NaHCO3. The
two
phases were separated; the aqueous phase was extracted with DCM. The combined
organic extracts were treated with excess Boc20, dried over Na2SO4, filtered
and
concentrated. The residue was purified by silica gel chromatography to give le
(0.8 g)
and Id (0.3 g).
Step 1D
[00113] A mixture of le (0.8 g), If (1.2 g), Na2CO3 (2 M, 5 ml), and
Pd(dppf)Cl2 (0.3 g)
in 1.4-dioxane(50 ml) was stirred in under N2 at 80 C for 20 h. After cooled
to room
temperature, the solvents were removed. The residue was purified by silica gel

chromatography to give colorless oil lg (0.8 g). MS (ESI): m/z=516 [M+H].
Step 1E
[00114] A mixture of lg (0.8 g) and N2H4 (8 ml) in Et0H (80 ml) was refluxed
for 28h.
After cooled to room temperature, the solvents were removed. The residue was
purified
by silica gel chromatography to give colorless oil lh (0.327 g). MS (ES!):
m/z=502
[M+H].
Step 1F
[00115] To a solution of 1 h (0.327 g) in DCM (15 ml) was added TFA (1.5 ml).
The
mixture was stirred at rt for 30 min and concentrated to give Ii which was
used directly
in next step.
Step 1G
[00116] To a solution of Ii (10.6 mg, 0.026 mmol) in DCM (2 ml) were added
Et3N (0.1
ml), acrylic acid (5 mg, 0.067 mmol) and HBTU (19 mg, 0.05 mmol). The
resulting
mixture was stirred at room temperature for 0.5 h and purified by reversed
phase
preparative HPLC to give title compound 1 (3.5 mg) as white solid. MS (ES1):
m/z =
456 [M-FH]+.
[00117] Examples 2 to 12 (Table 1) were made from lb and corresponding amines
(commercially available) via the similar conditions described in steps 1B-1G
of
Example 1.
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[00118] Table 1. Compounds of formula:
0S
NH2 =
Y I \
HN N
0 L"--y
, õ::, 7 .::;; :=; 1 . .1 , õ:: .: , i .::.i , ,
:ms(Esi) i
]Example 12.41 '''''' Name i' ''';'
rniz [M-4-H}
4-amino-3-(4-phenoxypheny1)-1-(1-1
2 N --(---- prop-2-enoy1-3-piperidy1)-6H-
pyrazolo[3,4-d]pyridazin-7-one 456
0
--E 4-amino-3-(4-phenoxypheny1)-1-
.....r:
3
CN [(3S)-1-prop-2-enoylpyrrolidin-3-
y1]-6H-pyrrolo[2,3-d]pyridazin-7- 442
one
0
..,-/...., 4-amino-3-(4-phenoxypheny1)-1-
[(3R)-1-prop-2-enoylpyrrolidin-3-
4 U..y, y1]-6H-pyrrolo[2,3-d]pyridazin-7- 442
one
0
.----7 4-amino-3-(4-phenoxypheny1)-1-(1-
prop-2-enoylazetidin-3-y1)-6H-
N
)/' //pyrrolo[2,3-d]pyridazin-7-one 428
0
4-amino-3-(4-phenoxypheny1)-1-
jt N¨/ [[(2S)-1-prop-2-enoylpyrrolidin-2-
6
yl]methy1]-6H-pyrrolo[2,3- 456
c)
\_ d]pyridazin-7-one
'PO 4-amino-3-(4-phenoxypheny1)-1-
[[(2R)-1-prop-2-enoylpyrrolidin-2-
7 N yl]methy1]-6H-pyrrolo[2,3- 456
1:- d]pyridazin-7-one
\_
4-amino-3-(4-phenoxypheny1)-1-
[(1-prop-2-enoylpyrrolidin-3-
8 0\1 yl)methy1]-6H-pyrrolo[2,3- 456
0 d]pyridazin-7-one
9 ---"--.)
N 4-amino-3-(4-phenoxypheny1)-1-(1-
prop-2-enoy1-4-piperidy1)-6H-
pyrrolo[2,3-d]pyridazin-7-one 456
,..,..,
0
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!Example L-Y Namek
m/z [M+Hr ;
1 4-amino-3-(4-phenoxypheny1)-1-
[(1-prop-2-enoy1-4-
piperidyl)methy1]-6H-pyrrolo[2,3- 470
N d]pyridazin-7-one
e...
'lli? N-((1s,4s)-4-(4-amino-7-oxo-3-(4-
phenoxypheny1)-6,7-dihydro-1H-
11
pyrrolo[2,3-d]pyridazin-1-
yl)cyclohexyl)acrylamide 470
HN.-C-----
0
4-amino-3-(4-phenoxypheny1)-1-
.."..'.7 [(1-prop-2-enoylazetidin-3-
12
yl)methy1]-6H-pyrrolo[2,3- 442
N /
d]pyridazin-7-one
0
[00119] Example 13. 1-(1-acryloy1-4-fluoropiperidin-3-y1)-4-amino-3-(4-
phenoxypheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
Cbz Cbz Cbz Cbz lb
NH4OH, 80 C A DAST ..A... HCI --11-, Et0Ac
. .
Boo,20 BocHN -78 C to rt BocHN-r _ H2N---r reflux
0 13a A 13OH B F L-
b 13c 13dF D
0 .
NC Br
NC,4
n I* o No :1
Et02e-N, Br2, CH2010 If pt -tni_11,-. .,2
NC
' EtO2C N l \ F.----UN-Cbz 00 F---an.... Pd(dppf)Cl2, K2003
Et02C N.,
13e E 13f " Cbz dioxane, 80 C F
F 13--g-UN-Cbz
0* 0* 0 =
NH2 NH2
K2CO3 NH2
H2NNH2 N, i \ Pd/C, H2 N õ
N CI HN N
G 13h OF_L-\ H OF 0
OF
NI-Cbz
131\NH I ''aN---e----
13 0
Step 13A
[00120] A mixture of 13a (2.2 g) and NH4OH (14 mL) in Et0H (33 mL) was stirred
in
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seal tube at 80 C for 18 h. The solvents were removed; the residue was
dissolved in
THF (30 mL) and Et0H (30 mL) and charged with Boc20 (2.46 g). The mixture was
stirred at room temperature for 20h. The crude product was purified by silica
gel
chromatography to give white solid 13b (1.02 g) and undesired region isomer
(1.7 g).
Step 13B
[00121] DAST (0.28 mL, 2.14 mmol) was added dropwise to a solution of 13b
(0.68g,
1.94 mmol) in DCM (20 mL) at -78 C. The mixture was allowed to warm to room
temperature overnight. It was quenched with saturated NaHCO3 solution,
extracted with
DCM. The organic extracts were dried over Na2SO4, filtered and concentrated.
The
residue was purified by silica gel chromatography to give colorless oil 13c
(0.31 g).
Step 13C
[00122] A mixture of 13c (0.31 g) and HCI (4 M in dioxane) was stirred for 2h.
The
solvents were removed, the residue was suspended in Et0Ac, 2M K2CO3 solution
was
added to adjust pH over 9. The aqueous layer was extracted with Et0Ac three
times.
The combined organic extracts were dried over Na2SO4, filtered and
concentrated to
give light yellow oil 13d (0.18 g).
Step 13D
[00123] To a solution of 13d (140 mg) in Et0Ac (12 ml) at 60 C was added
dropwise a
solution of lb (140 mg) in Et0Ac (3 ml). The mixture was refluxed for 18h.
After cooled
to room temperature, the solvents were removed. The residue was purified by
silica gel
chromatography to afford yellow oil 13e (40 mg).
Step 13E
[00124] To a solution of 13e (40 mg) and AcOH (40 pl) in DCM (3 ml) at 0 C was

added Br2 (40 mg) slowly. The mixture was allowed to warm to rt and stirred
for 5 h, and
then quenched with a solution of 10% Na2S203 and saturated solution of NaHCO3.
The
two phases were separated; the aqueous phase was extracted with Et0Ac. The
combined organic layer was dried over Na2SO4, filtered and concentrated. The
residue
was purified by silica gel chromatography to give 13f (18 mg).
Step 13F
[00125] A mixture of 13f (22 mg), If (25 mg), K2CO3 (2 M, 0.1 ml), and
Pd(dppf)C12
SUBSTITUTE SHEET (RULE 26)

- 24 -
(13 mg) in 1.4-dioxane(1 ml) was stirred in under N2 at 80 C for 20 h. After
cooled to
room temperature, the solvents were removed. The residue was purified by
silica gel
chromatography to give colorless oil 13g (28 mg). MS (ESI): m/z=568 [M+Hr.
Step 13G
[00126] A mixture of 13g (28 mg) and N2H4 (0.2 ml) in Et0H (2 ml) was refluxed
for
two days. After cooled to room temperature, the solvents were removed. The
residue
was purified by silica gel chromatography to give 13h (15mg). MS (ESI):
m/z=554
[M+H].
Step 13H
[00127] A mixture of 13h (15 mg) and Pd/C (10vvt%, 9 mg) in Me0H (1 ml) was
stirred
under H2 balloon for 3 h. The reaction mixture was filtered through a pad of
celiteml,
washed with Et0Ac/Me0H and concentrated to give white solid 131 (10mg).
Step 131
[00128] To a mixture of 13i (5.3 mg) and K2CO3 (2M, 30 pl) in THF (0.8 ml) at
0 C was
added a solution of acryloyl chloride (1.4 mg) in THF. The resulting mixture
was stirred
at 0 C for 0.5 h and purified by reversed phase preparative HPLC to give title
compound
13 (3 mg) as off white solid. MS (ESI): m/z = 474 [M+H]
[00129] Example 14. (R)-1-(1-acryloy1-.5,5-difluoropiperidin-3-y1)-4-
amino-3-(4-
phenoxypheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
NC NC NC
, Br
- A
lb
EtO2C-'--N Pd(OH)2/C EtO2C'--N 1) Er2 Et02c¨N
6n Et0Ac, reflux N-3n H2 NH 2) F- --/ Boc20
14a A F14b
14c F
14d
0 o 41k.
= , NH2 NH2
1f B4O,2 NC 1) HCI
H2NNH2 N
I , N
Pd(dppf)C12, Na2CO3 Et0H,reflux N 2) K2CO3 HN N
EtO2C N
dioxane, 80 C E 0 0
14e
FN-Boc 14f F N-Boc 0
14 0
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- 25 -
Step 14A
[00130] To a solution of lb (271 mg) in Et0Ac (12 ml) at 60 C was added
dropwise a
solution of 14a (223 mg, the compound was prepared following procedures
described in
Organic Letters, 2011, vol. 13, p.4442-4445 Anne Cochi et al.) in Et0Ac (2
ml). The
mixture was refluxed for 18 h. After cooled to room temperature, the solvents
were
removed. The residue was purified by silica gel chromatography to afford light
yellow oil
14b (76 mg).
Step 14B
[00131] A mixture of 14b (65 mg) and Pd(OH)21C (10wt%, 50 mg) in Me0H/THF (3/1

ml) was stirred under H2 balloon for 20 h. The reaction mixture was filtered
through a
pad of celiteTM, washed with Et0Ac/Me0H and concentrated. The residue was
purified
by silica gel chromatography to afford white solid 14c (38 mg).
Step 14C
[00132] To a solution of 14c (38 mg) in DCM (3 ml) at 000 was added Br2 (15
pl)
slowly. The mixture was stirred at rt for 18 h. Excess TEA and Boc20 were
added. The
resulting mixture was stirred at rt for 24 h. Water was added, and the mixture
was
extracted with Et0Ac. The organic extracts were washed with brine, dried over
Na2SO4,
filtered and concentrated. The residue was purified by silica gel
chromatography to give
14d (20 mg).
Step 14D
[00133] A mixture of 14d (20 mg), if (19 mg), 1<2003 (2M, 0.1 ml), and
Pd(dppf)0I2 (7
mg) in 1.4-dioxane(1.5 ml) was stirred in under N2 at 80 C for 3 h. After
cooled to room
temperature, the solvents were removed. The residue was purified by silica gel

chromatography to give colorless oil 14e (30 mg). MS (ESI): m/z=552 [M+H].
Step 14E
[00134] A mixture of 14e (30 mg) and N2H4 (0.25 ml) in Et0H (2.5 ml) was
refluxed for
20 h. After cooled to room temperature, the solvents were removed. The residue
was
purified by silica gel chromatography to give white solid 14f (15mg). MS
(ESI): m/z=538
[M+H]+.
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Step 14F
[00135] A mixture of 14f (15 mg) and HC1 solution (1 ml, 4M in dioxane) was
stirred at
rt for 2h and concentrated to give 14g (22 mg)which was used directly in next
step
without further purification. To a mixture of 14g (13 mg) and K2CO3 (2 M, 40
pl) in THF
(1 ml) at 0 C was added a solution of acryloyl chloride (4 mg) in THF. The
resulting
mixture was stirred at 0 C for 20 min and purified by reversed phase
preparative HPLC
to give title compound 14 (3.3 mg) as white solid. MS (ESI): miz = 492 [M+H]+.

[00136] Intermediate 1. tert-butyl (3-a minobicyclo[3.2.1]octan-8-yl)carbamate
0
) Me 0 NH2 NHBoc
iN lib'Br 1) NaOH NN4Ac 1) Boc20
____ Et3N, õ
Me 2) DPPA, NaCNBH3 Y 2) Pd/C, H2
BnOH NHCbz NHCbz NH2
ha A 11 c B Ile
lid 11
Step 11A
[00137] Methyl 3-bromo-2-(bromomethyl)propanoate lib (2.61 g) was added
dropwise to a solution of 1-(cyclopent-1-en-1-yl)pyrrolidine ha (1.44 g),
Et3N(1.46 ml) in
CH3CN (10 ml). The mixture was refluxed for 20 h. A solution of 5% AcOH in
water (1m1)
was added. The mixture was refluxed for 1.5 h. After cooled to room
temperature,
Et0Ac (15 ml) was added. The suspension was filtered. The resulting filtrate
was
treated with water, extracted with Et0Ac. The combined organic extracts were
washed
with brine, dried over Na2SO4, filtered and concentrated. The residue was
purified by
silica gel chromatography to afford I1c (1.0 g).
Step I1B
[00138] A mixture of I1c (1.0 g), 2M NaOH (10 ml) and Me0H (5 ml) was stirred
at
room temperature for 1.5 h. The mixture was acidified and extracted with
Et0Ac. The
combined organic layers were washed with brine, dried over Na2SO4, filtered
and
concentrated. The resulting oil was dissolved in toluene (14 ml) followed by
adding
DPPA(1.7 g) and Et3N (0.84 ml). The mixture was stirred at room temperature
for 1.5h
and heated to 110 C for 2h. After addition of BnOH (5.7 ml), the mixture was
stirred at
110 C for 2 days. The mixture was diluted with Et0Ac and washed with brine,
dried
over Na2SO4, filtered and concentrated. The residue was purified by silica gel

chromatography to afford lid (3.0 g).
SUBSTITUTE SHEET (RULE 26)

- 27 -
Step IIC
[00139] To a solution of lid (0.5 g), NH40Ac (0.7 g) in CH3OH (5 ml) was added

NaCNBH3 (0.23 g). The mixture was stirred at rt for 2 h. It was quenched with
saturated
NaHCO3 solution, extracted with DCM. The organic extracts were dried over
Na2SO4,
filtered and concentrated. The residue was purified by silica gel
chromatography to give
lie (45 mg).
Step I1D
[00140] A mixture of lie (0.24 g) and Boc20 (1.2 g) in DCM (10 ml) was stirred
at rt for
20 h. After evaporation of solvents under reduced pressure, the residue was
purified by
silica gel chromatography to give 0.14 g colorless oil. The oil was dissolved
in Me0H
(15 ml) and charged with Pd/C. The mixture was stirred under H2 balloon for 20
h, filter
through a pad of celiteTM and concentrated to give 11 (66mg). MS (ESI): m/z =
241
[M+H] +.
[00141] Example 15. N-(3-(4-amino-7-oxo-3-(4-phenoxyphenyI)-6,7-dihydro-1H-

pyrrolo[2 ,3-d]pyridazin-1-yl)bicyclo[3.2.1]octan-8-yl)acrylam ide
0 4,
NH2
1
HL N
0 0

0
[00142] Title compound 15 (light yellow solid, 4.8 mg) was made from lb and 11
via
the similar conditions described in steps 1B-1G of Example 1. MS (EST m/z =
496
[M+H] +.
[00143] Example 16. 4-amino-1-[(3R)-1-[(E)-4-[isopropyl(methyl)amino]but-2-
enoy1]-3-
piperidy1]-3-(4-phenoxypheny1)-6H-pyrrolo[2,3-d]pyridazin-7-one
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0*
HN/ NH2
MeOBr
______________ Me0 _________ . HO HN ' N
0 0 HATU
A 0 0
16a 16b 16c
16 0
Step 16A
[00144] A mixture of 16a (225 mg) and N-methylpropan-2-amine (190 mg) in THF
(3
ml) was stirred at rt for two days. Saturated NaC1 solution was added, the
mixture was
extracted with Et0Ac twice. The organic extracts were washed with brine, dried
over
Na2SO4, filtered, and concentrated to give 16b (200 mg).
Step 16B
[00145] To a solution of 16b (195 mg) in THF (5 ml) was added LiOH (1M
solution, 2.5
ml). The mixture was stirred at rt for 2 h. 2M HC1 solution was added to pH
<5,
concentrated to give 16c (500 mg).
Step 16C
[00146] To a solution of 1i (11 mg) in DMF (1 ml) was added D1EA (0.05 ml),
acid 16c
(15 mg) and HATU (20 mg). The resulting mixture was stirred at room
temperature for
1.5 h. The solvents were removed, and the residue was purified by reversed
phase
preparative HPLC to give title compound 16 (4 mg). MS (ESI): m/z = 541 [M+H].
[00147] Example 17. tert-butyl N-RE)-4-[(3R)-3-[4-amino-7-oxo-3-(4-
phenoxypheny1)-
6H-pyrrolo[2,3-d]pyridazin-1-y1]-1-piperidy1]-4-oxo-but-2-enyl]-N-methyl-
carbamate
0*
NH2
MeNH2 LiOH
Me02C Me02C H HO--õ Boc
Boc,20 HBTU HN N
16a A 17a 17b
0
17 Boc
0
SUBSTITUTE SHEET (RULE 26)

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Step 17A
[00148] To a mixture of 16a (0.43 g) in THF at -60 C was added dropwise a
solution
of 2M methylamine in THF (3 m1). The mixture was stirred at -60 C for 2 h and

concentrated. The residue was purified by silica gel chromatography to give
17a (0.146
g).
Step 17B
[00149] To a solution of 17a (145 mg) in THE (5 ml) was added NaOH (2 M
solution,
2m1) and Me0H(0.5 ml). The mixture was stirred at rt for 35 min. 1M HC1
solution was
added to pH <5, concentrated. The crude product was dissolved in DCM/Me0H and
treated with Boc20 (0.5 g). The mixture was stirred at rt for 2 h and
concentrated. The
residue was purified by silica gel chromatography to give 17b (0.11 g).
Step 170
[00150] To a solution of 1i (10 mg) in DCM (2 ml) were added Et3N (0.1 ml),
acid 17b
(7 mg) and HBTU (18 mg). The resulting mixture was stirred at room temperature
for
0.5 h and purified by silica gel chromatography to give title compound 17 (10
mg) as off
white solid. MS (ES1): m/z = 599 [M+H].
[00151] Example 18. 4-amino-1-[(3R)-1-[(E)-4-(methylamino)but-2-enoy1]-3-
piperidy1]-
3-(4-phenoxypheny1)-6H-pyrrolo[2,3-d]pyridazin-7-one
0 =
NH2 49
N \
HIV I N
0 tNz--N/
18
0
[00152] To a solution of compound 17 (6 mg) in DCM (1.6 ml) was added TFA
(0.2m1).
The mixture was stirred at it for 30 min and concentrated. The residue was
purified by
reversed phase preparative HPLC to give title compound 18 (2.4 mg) as white
solid.
MS (ES1): m/z = 499 [M+H].
[00153] Example 19. 4-amino-3-(4-phenoxypheny1)-1-(1-propionylpiperidin-3-y1)-
1H-
pyrrolo[2,3-d]pyridazin-7(6H)-one
SUBSTITUTE SHEET (RULE 26)

- 30 -
46
o
NH2
Hti\I N
0
19
o
[00154] A mixture of compound 2 (5 mg) and Pd/C (10wt%, 5 mg) in Me0H (5 ml)
was
stirred under H2 balloon for 3h. The reaction mixture was filtered through a
pad of
celiteTM, washed with Et0Ac/Me0H and concentrated to give title compound 19
(2.7 mg)
as white solid. MS (ESI): miz = 458 [M+H]t
[00155] Example 20. (R)-3-(4-amino-7-oxo-3-(4-phenoxyphenyI)-6,7-dihydro-
1H-
pyrrolo[2,3-d]pyridazin-1-yl)piperidine-1-carbonitrile
o =
NH2
HIV N
0
20 L\N-CN
[00156] To a mixture of 11(3.5 mg) and K2CO3 (2M, 15 pl) in acetone (3 ml) was

added BrCN (1 mg). The mixture was stirred at rt for 2 h and concentrated. The
residue
was purified by reversed phase preparative HPLC to give title compound 20 (1.6
mg) as
white solid. MS (ESI): m/z = 427 [M+H].
[00157] Example 21. 4-amino-1-(1-(but-2-ynoyl)piperidin-3-y1)-3-(4-
phenoxypheny1)-
1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
,
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Mt
0
NH2 11#
N \
HN I
021 tN/
[00158] The title compound was made from racemic Ii and but-2-ynoic acid via
the
similar conditions described in step 1G of Example 1. MS (ES1): m/z = 468 [M4-
H].
[00159] Examples 22 to 37 (Table 2) were made from Ii and corresponding acids
(commercially available or easily prepared) via the similar conditions
described in
Examples 16, 17, 18.
[00160] Table 2. Compounds of formula:
41,
0
NH2 Iht
r I \
HN
0
L\N
MS(ES1)
Example Z Name
m/z [M+H]
ci 4-amino-1-[(3R)-1-(2-ch loroacety1)-
22 3-piperidy1]-3-(4-phenoxypheny1)- 478
O 6H-pyrrolo[2,3-d]pyridazin-7-one
4-amino-1-[(3R)-1-
23
(cyclopropanecarbonyI)-3-
piperidy1]-3-(4-phenoxypheny1)-6H- 470
O pyrrolo[2,3-d]pyridazin-7-one
NC 3-[(3R)-3-[4-amino-7-oxo-3-(4-
24
phenoxypheny1)-6H-pyrrolo[2,3-
469
d]pyridazin-1-y1]-1-piperidy1]-3-oxo-
O propanenitrile
SUBSTITUTE SHEET (RULE 26)

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Example Z Name MS(ES1)
m/z [M i-H]
4-amino-1-[(3R)-1-[( E)-but-2-
25 i__{,¨,.....y
enoy1]-3-piperidy1]-3-(4-
ph enoxyph eny1)-6 H-pyrrolo[2, 3- 470
0
d]pyridazin-7-one
/ 4-amino-1-[(3R)-1-[(E)-4-
26 1.....(----7-N (dimethylamino)but-2-enoyI]-3-
\ 513
piperidy1]-3-(4-phenoxypheny1)-6H-
O pyrrolo[2,3-d]pyridazin-7-one
\ 4-amino-1-[(3R)-1-[(E)-4-
27 ...z.../.... --N/ (diethylamino)but-2-enoy1]-3-
541
piperidyI]-3-(4-phenoxypheny1)-6H-
O pyrrolo[2,3-d]pyridazin-7-one
4-amino-1-[(3R)-1-[(E)-4-
28 N (cyclopropylamino)but-2-enoyI]-3-
H piperidyI]-3-(4-phenoxypheny1)-6H- 525
O pyrrolo[2,3-d]pyridazin-7-one
. 4-amino-1-[(3R)-1-[(E)-4-
(cyclopropyl(methyl)ami no)but-2-
29 ....f-Np enoy1]-3-piperidy1]-3-(4- 539
ph enoxyph eny1)-6 H-pyrrolo[2,3-
O d]pyridazin-7-one
4-amino-1-[(3R)-1-[(E)-4-
[cyclopropyl(ethyl)amino]but-2-
30 . enoy1]-3-piperidy1]-3-(4- 553
\--- ph enoxyph eny1)-6 H-pyrrolo[2,3-
O d]pyridazin-7-one
/0 4-amino-1-[(3R)-1-[(E)-4-
[cyclobutyl(methyl)amino]but-2-
31 õy"-N enoy1]-3-piperidy1]-3-(4- 553
\
ph enoxyph eny1)-6 H-pyrrolo[2,3-
O d]pyridazin-7-one
0 4-amino-1-[(3R)-1-[(E)-4-
[cyclohexyl(methyl)ami no]but-2-
i....,(---....../"-N
\ enoy1]-3-piperidy1]-3-
(4-
ph enoxyph eny1)-6 H-pyrrolo[2,3- 581
32
O d]pyridazin-7-one
,\ 4-amino-1-[(3R)-1-[(E)-4-(azetidin-
33 1....1(------/"--N\,) 1-yl)but-2-enoy1]-3-piperidy1]-3-(4-
525
ph enoxyph eny1)-6 H-pyrrolo[2, 3-
O d]pyridazin-7-one
4-amino-3-(4-phenoxypheny1)-1-
34 ="---:-.--/¨NO [(3R)-1-[(E)-4-pyrrolidin-1-ylbut-2-
539
enoy1]-3-piperidy1]-6H-pyrrolo[2,3-
O d]pyridazin-7-one
SUBSTITUTE SHEET (RULE 26)

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Example Z Name MS(ESI)
m/z [M+H]
4-amino-1-[(3R)-1-[(E)-4-
morpholinobut-2-enoyI]-3-
35 555
o piperidyI]-3-(4-phenoxypheny1)-6H-
pyrrolo[2,3-d]pyridazin-7-one
4-amino-1-[(3R)-1-[(E)-4-(4-
36 methylpiperazin-l-yl)but-2-enoyIF
568
o 3-piperidyI]-3-(4-phenoxypheny1)-
6H-pyrrolo[2,3-d]pyridazin-7-one
z 4-amino-1-[(3R)-1-[(E)-4-
37 O methoxybut-2-enoyI]-3-piperidy1]-3-
500
(4-phenoxyphenyI)-6H-pyrrolo[2,3-
0 d]pyridazin-7-one
[00161] Examples 38 to 49 (Table 3) were made from (E)-4-(dimethylamino)but-2-
enoic acid and corresponding amines (precursors of previous examples) via the
similar
conditions described in step 160 of Example 16.
[00162] Table 3. Compounds of formula:
0*
NH2
N \
HN I N
o L"--Y
Example L-Y Name MS(ESI)
m/z [M+N+
4-amino-141-[(E)-4-
N/ (dimethylamino)but-2-enoy1]-3-
38 513
\ piperidy1]-3-(4-phenoxyphenyl)-
o 6H-pyrrolo[2,3-d]pyridazin-7-one
4-amino-1-[(3R)-1-[(E)-4-
(dimethylamino)but-2-
39 enoyl]pyrrolidin-3-yI]-3-(4- 499
y 'N" phenoxyphenyI)-6H-pyrrolo[2,3-
o d]pyridazin-7-one
/ 4-amino-1-[1-[(E)-4-
N¨

(dimethylamino)but-2-
enoyl]azetidin-3-yI]-3-(4- 485
N
o
phenoxyphenyI)-6H-pyrrolo[2,3-
d]pyridazin-7-one
SUBSTITUTE SHEET (RULE 26)

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Example L-Y Name MS(ES1)
m/z [M+H]+
4-amino-1-[[(2S)-1-[(E)-4-
(,N
(dimethylamino)but-2-
1\i¨/ enoyllpyrrolidin-2-yllmethyl]-3-(4-
41 0 phenoxypheny1)-6H-pyrrolo[2,3- 513
\¨N/ d]pyridazin-7-one
\
4-amino-1-[[(2R)-1-[(E)-4-
(dimethylamino)but-2-
enoyllpyrrolidin-2-yllmethyl]-3-(4-
42 ci phenoxypheny1)-6H-pyrrolo[2,3- 513
\¨N/ d]pyridazin-7-one
\
4-amino-1-[[1-[(E)-4-
\
7 ¨ (dimethylamino)but-2-
43 N enoyl]pyrrolidin-3-yl]methy1]-3-(4- 513
0 ' phenoxypheny1)-6H-pyrrolo[2,3-
d]pyridazin-7-one
4-amino-1-[1-[(E)-4-
(dimethylamino)but-2-enoy1]-4-
piperidy1]-3-(4-phenoxypheny1)- 513
N N, 6H-pyrrolo[2,3-d]pyridazin-7-one
__,--/
0
, 4-amino-1-[1-[(E)-4-
...{...y---N' (dimethylamino)but-2-enoy1]-4-
45 F N \ fluoro-3-piperidyI]-3-(4- 531
0 phenoxypheny1)-6H-pyrrolo[2,3-
d]pyridazin-7-one
(E)-N-[4-[4-amino-7-oxo-3-(4-
phenoxypheny1)-6H-pyrrolo[2,3-
46 / d]pyridazin-1-yl]cyclohexyl]-4- 527
(dimethylamino)but-2-enamide
HN
0
4-amino-1-[[1-[(E)-4-
47 Sc \
N¨ (dimethylamino)but-2-
enoyl]azetidin-3-yl]methy1]-3-(4- 499
N ,¨/ phenoxypheny1)-6H-pyrrolo[2,3-
d]pyridazin-7-one
0
(E)-N-[3-[4-amino-7-oxo-3-(4-
phenoxypheny1)-6H-pyrrolo[2,3-
48 / d]pyridazin-1-y1]-8- 553
r/¨N\ (tneyClt0431.a2m.1i1n00 2 C)1baunty-1114
e-
HN namide
0
SUBSTITUTE SHEET (RULE 26)

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MS(ESI)
Example L-Y Name
m/z [M+H]+
4-amino-1-[(3R)-1-[(E)-4-
F N N\ (ddi fi irnu el! oh -y3Ia_ pMi pi neOri)dbyUi it-
-23747y11-5, 5-
49 549
0 phenoxyphenyI)-6H-pyrrolo[2,3-
d]pyridazin-7-one
[00163] Example 50. (E)-2-[(3R)-3-[4-amino-7-oxo-
3-(4-phenoxyphenyI)-6H-
pyrrolo[2,3-d]pyridazin-1-yl]piperidine-1-carbony1]-3-cyclopropyl-prop-2-
enenitrile
11
NH2 *
N
I I
HN
0
0
[00164] To a mixture of compound 24 (9 mg) and piperidine (2 mg) in Me0H (1
ml)
was added cyclopropanecarbaldehyde (2.1 mg). The mixture was stirred at rt for
20h
and concentrated. The residue was purified by reversed phase preparative HPLC
to
give title compound 50 (2.7 mg) as white solid. MS (ESI): m/z = 521 [M+H].
[00165] Example 51. 1-(1-acryloylpiperidin-3-y1)-
4-amino-3-(4-methoxypheny1)-1H-
pyrrolo[2,3-d]pyridazin-7(6H)-one
NH2
Y' I\
HN
tN
51
0
[00166] The title compound was made was made from racemic le and (4-
methoxyphenyl)boronic acid via the similar conditions described in steps 1D-1G
of
Example I. MS (ES I): m/z = 394 [M+H].
[00167] Example 52. 4-amino-141 -[(E)-4-(d imethylamino)but-2-enoyI]-3-
piperidy1]-3-
SUBSTITUTE SHEET (RULE 26)

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(4-methoxypheny1)-6H-pyrrolo[2,3-d]pyridazin-7-one
0¨

NH2
N
I
HN
0
52
0
[00168] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 51) via the similar conditions
described
in step 16C of Example 16. MS (ES1): tri/z = 451 [M-FH]f.
[00169] Example 53. 1-(1-
acryloylpiperidin-3-y1)-4-amino-3-(3-chloro-4-
methoxypheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
0-
40, a
NH2
N \
HN
0
53
0
[00170] The title compound was made was made from racemic le and (3-chloro-4-
methoxyphenyOboronic acid via the similar conditions described in steps 1D-1G
of
Example 1. MS (ES I): m/z = 428 [M+H].
[00171] Example 54. 4-amino-3-
(3-chloro-4-methoxy-pheny1)-1-[1-[(E)-4-
(dimethylamino)but-2-enoy11-3-piperidy11-6H-pyrrolo[2,3-d]pyridazin-7-one
0¨

., CI
NH2
N
I
HN
054
0
[00172] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 53) via the similar conditions
described
SUBSTITUTE SHEET (RULE 26)

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in step 16C of Example 16. MS (ESI): m/z = 485 [M+H].
[00173] Example 55. 1-(1-
acryloylpiperidin-3-yI)-4-amino-3-(4-(2-
fluorophenoxy)phenyI)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
0
NH2 Ili
HN
0
of

[00174] The title compound was made from racemic le and ((4-(2-
fluorophenoxy)phenyl)boronic acid via the similar conditions described in
steps 1D-1G
of Example 1. MS (ESI): m/z = 474 [M+H].
[00175] Example 56. (R)-1-(1-
acryloylpiperidin-3-yI)-4-amino-3-(4-(2-
fluorophenoxy)phenyI)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
0
NH2
N \
HN
0
56
0
[00176] The title compound was made was made from le and ((4-(2-
fluorophenoxy)phenyl)boronic acid via the similar conditions described in
steps 1D-1G
of Example 1. MS (ESI): m/z = 474 [M+H].
[00177] Example 57. 4-amino-1-
[(3R)-1-RE)-4-(dimethylamino)but-2-enoyl]-3-
piperidyI]-3-[4-(2-fluorophenoxy)pheny1]-6H-pyrrolo[2,3-d]pyridazin-7-one
SUBSTITUTE SHEET (RULE 26)

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F
0 4k
NH2 41k
r \
HN
0 LN r\j(
57
0
[00178] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 56) via the similar conditions
described
in step 16C of Example 16. MS (ESI): m/z = 531 [M+H]+.
[00179] Intermediate 2.
40
K2CO3
Fe F NaNO2F F F F +
46
ti.j
CuBr L,
OH NO2 A NO2 B
12a 12b NH2 C Br D
12c 12 0 __
Step I2A
[00180] A mixture of 2,6-difluorophenol (3.0 g, 21.3 mmol), 1-fluoro-4-
nitrobenzene
(3.04 g, 23.4 mmol) and K2003(4.4 g, 32 mmol) in CH3CN (50 ml) was refluxed 16
h.
After cooled to room temperature, the solvents were removed. Water was added,
the
mixture was extracted with Et0Ac three times. The organic extracts were washed
with
water, brine, dried over MgSO4, filtered, and concentrated to give oil I2a
(4.9 g).
Step I2B
[00181] A mixture of 1,3-difluoro-2-(4-nitrophenoxy)benzene I2a (4.9 g, 19.5
mmol),
saturated NH40I solution (5 ml) and iron powder (5.5 g, 97.5 mmol) in Me0H(40
mL)
was refluxed for 3 h. The mixture was filtered. Water was added to the
filtrate, extracted
with Et0Ac three times. The organic extracts were washed with water, brine,
dried over
MgSO4, filtered, and concentrated to give light yellow oil 12b (4.1g). MS
(ESI):
m/z=222.1
SUBSTITUTE SHEET (RULE 26)

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Step I2C
[00182] To a mixture of 4-(2,6-difluorophenoxy)aniline 12b (4.1 g, 18.5 mmol)
in 2M
H2SO4 solution (50 ml) at 0 C was added a solution of NaNO2(6.4 g, 92.7 mmol)
in
water (20 m1). The mixture was stirred at 0 C for 40min and charged with CuBr
(5.3 g,
37 mmol). The resulting mixture was refluxed for 16 h, cooled to rt, extracted
with Et0Ac
three times. The organic extracts were washed with water, brine, dried over
MgSO4,
filtered, and concentrated to give colorless oil I2c (1.6 g).
Step I2D
[00183] A mixture of 2-(4-bromophenoxy)-1,3-difluorobenzene I2c (1.6 g, 3.6
mmol),
bis(pinacolato)-diboron (1.71 g, 6.7 mmol), KOAc (830 mg, 8.4 mmol) and
Pd(PPh3)20I2(126 mg, 0.18 mmol) in 1,4-dioxane (40 ml) was stirred in under N2
at 80
C for 16h. After cooled to room temperature, the solvents were removed. The
residue
was purified by silica gel chromatography to give colorless oil 12 (1.6 g).
[00184] Intermediate 3. 2-(4-(4-chlorophenoxy)pheny1)-4,4,5,5-tetramethy1-
1,3,2-
dioxaborolane
40 0
CI
13 0
[00185] A mixture of 1-chloro-4-(4-iodophenoxy)benzene (330 mg),
bis(pinacolato)diboron (508 mg), KOAc (300 mg) and Pd(PPh3)2Cl2(82 mg) in 1,4-
dioxane (10 ml) was stirred in seal tube under N2 at 100 C for 16h. After
cooled to
room temperature, filtered off solids, the filtrate was concentrated. The
residue was
purified by silica gel chromatography to give yellow oil 13 (150 mg).
[00186] Intermediate 4. 2-(4-(4-fluorophenoxy)pheny1)-4,4,5,5-tetramethy1-
1,3,2-
dioxaborolane
is 0
V(72/-
14
[00187] The title compound was made was made from 1-fluoro-4-(4-
iodophenoxy)benzene via the similar conditions described in Intermediate 3.
[00188] Intermediate 5. 2-(4-(3-fluorophenoxy)pheny1)-4,4,5,5-tetramethy1-
1,3,2-
SUBSTITUTE SHEET (RULE 26)

- 40 -
dioxaborolane
F 0
14111 Bto
15 6
[00189] A mixture of (3-fluorophenyl)boronic acid (0.71 g), 4-(4,4,5,5-
tetramethyl-
1,3,2-dioxaborolan-2-yl)phenol (1.02 g), Cu(OAc)2 (1.0 g), TEA (1.3m1), and
molecular
sieve 4A (3 g) in DCM (20 ml) was stirred at rt for 24h. The reaction mixture
was filtered
through a pad of celiteTM, washed with DCM and concentrated. The residue was
purified
by silica gel chromatography to give colorless oil 15 (60 mg).
[00190] Intermediate 6. 2-(4-(3-chlorophenoxy)pheny1)-4,4,5,5-tetramethyl-
1,3,2-
dioxaborolane
ci 0
$0 Bto
16 O
[00191] The title compound was made was made from (3-chlorophenyl)boronic acid

via the similar conditions described in Intermediate 5.
[00192] Intermediate 7. 2- (4-(3-
chlorophenoxy)-3-m ethoxyphenyI)-4 ,4,5 ,5-
tetram ethy1-1,3,2-dioxaborolane
0...
ci lio 0
B 0
17 Ot
[00193] The title compound was made was made from 3-chlorophenol and 1-fluoro-
2-
methoxy-4-nitrobenzene via the similar conditions described in Intermediate 2.
[00194] Intermediate 8. 2-(4-(3,4-
dichlorophenoxy)-3-methoxypheny1)-4,4,5,5-
tetram ethyl- 1 ,3, 2-d ioxabo rolane
o'
ci o
CI 137_
18 \
0
[00195] The title compound was made was made from 3,4-dichlorophenol and 1-
CA 2953798 2018-07-26

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fluoro-2-methoxy-4-nitrobenzene via the similar conditions described in
Intermediate 2.
[00196] Intermediate 9. 2-(4-(2-chloro-6-fluorophenoxy)phenyI)-4,4,5,5-
tetramethyl-
1,3,2-dioxaborolane
0 _c
CI
19
[00197] The title compound was made was made from 2-chloro-6-fluorophenol and
1-
fluoro-4-nitrobenzene via the similar conditions described in Intermediate 2.
[00198] Intermediate 10. 2-(4-(2-chlorophenoxy)pheny1)-4,4,5,5-tetramethy1-
1,3,2-
dioxaborolane
So

CI 110 137._
0
[00199] The title compound was made was made from 2-chlorophenol and 1-fluoro-
4-
nitrobenzene via the similar conditions described in Intermediate 2.
[00200] Intermediate 11. 2-(2-fluoro-4-phenoxypheny1)-4,4,5,5-tetramethy1-
1,3,2-
dioxaborolane
o0F
0 0
111
[00201] The title compound was made was made from phenol and 2,4-difluoro-1-
nitrobenzene via the similar conditions described in Intermediate 2.
[00202] Intermediate 12. (3-fluoro-4-phenoxyphenyl)boronic acid
0
B-OH
112 OH
[00203] To a solution of 4-bromo-2-fluoro-1-phenoxybenzene (0.5 g, 3.6 mmol)
in THF
(20 ml) at -78 C was added dropwise a solution of n-BuLi (2.5 M in hexane,
2.16 ml, 5.4
mmol). After 30min, triisopropyl borate (1.15 ml, 5.4 mmol) was added
dropwise. The
mixture was stirred -78 C for 1 h. The reaction was quenched with water,
extracted with
SUBSTITUTE SHEET (RULE 26)

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Et0Ac three times. The combined organic extracts were washed with water,
brine,
dried over MgSO4, filtered, and concentrated to give light yellow oil 112
(0.18 g).
[00204] Example 58. (R)-1-(1-
acryloylpiperidin-3-y1)-4-amino-3-(4-(2, 6-
d ifluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
0 0 0 41,
12
Br Pd2(dba)3,
N2I-14
p(cy)3 N,NH2 NH2
,1

EtO2C dioxane NC 1) TFA
I \ I \
DC HN N
EtO2C N Et0H, refl UX rill N
2) E I
le NBoc 0 0
A 58a aNBoc
58ba NBoc 0
8 0
Step 58A
[00205] A mixture of le (2.8 g, 6.6 mol), 12 (2.2 g, 6.6 mol) and K3PO4-3H20
(2.6g,
9.9 mol) in 1.4-dioxane/water (10 m1/1 ml) was degassed with N2. Next was
added
Pd2(dba)3(300mg, 0.33 mmol) and P(Cy)3 (185 mg, 0.66 mmol). The resulting
mixture
was refluxed under N2 for 16h. After cooled to room temperature, the solid was
filtered
off, the filtrate was concentrated. The residue was purified by silica gel
chromatography
to give white solid 58a (1.2 g). MS (ES I): m/z=552 [M-FH]+.
Step 58B
[00206] A mixture of 58a (1.2 g) and N21-14.H20 (1 mL) in Et0H (5 ml) was
refluxed for
16h. After cooled to room temperature, the solvents were removed. The residue
was
purified by silica gel chromatography to give white solid 58b (0.66 g). MS
(ES1):
m/z=538 [M-FH]+.
Step 58C
[00207] To a solution of 58b (880 mg, 1.63 mol) in DCM (5 ml) was added TFA (1
ml).
The mixture was stirred at rt for 3 h and concentrated to give oil 58c (940
mg). To a
solution of 58c (940 mg) in DCM (5 ml) was added acrylic acid (210 mg, 2.5
mol), EDC1
(627 mg, 3.3 mmol) and TEA (340 mg, 3.3 mmol). The resulting mixture was
stirred at
room temperature for 18 h and concentrated. The residue was purified by silica
gel
chromatography to give the title compound 58 (450 mg) as white solid. MS
(ES1): tniz =
492 [M+H]+.
SUBSTITUTE SHEET (RULE 26)

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[00208] Example 59. 4-amino-344-
(2,6-difluorophenoxy)pheny1]-1-[(3R)-1-[(E)-4-
(dimethylamino)but-2-enoy1]-3-piperidy1]-6H-pyrrolo[2,3-d]pyridazin-7-one
0
NH2 F
N \
HN
0
L\NN\
59 0
[00209] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and amine 58c via the similar conditions described in step 160 of Example 16.
MS (ES!):
m/z = 549 [M-'-H].
[00210] Example 60. 1-(1-
acryloylpiperidin-3-yI)-4-amino-3-(4-(4-
fluorophenoxy)phenyI)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
0 40, F
NH2 46.
N \
HN
0
of

[00211] The title compound was made was made from racemic le and intermediate
4
via the similar conditions described in steps 1D-1G of Example 1. MS (ESI):
m/z = 474
[00212] Example 61. 4-amino-141 -[(E)-4-(dimethylamino)but-2-enoy1]-3-
piperidy1]-3-
[4-(4-fluorophenoxy)pheny1]-6H-pyrrolo[2,3-d]pyridazin-7-one
SUBSTITUTE SHEET (RULE 26)

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o 41k F
NH2 411k
N \
HN
0
61
0
[00213] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 60) via the similar conditions
described
in step 16C of Example 16. MS (ESI): m/z = 531 [M+H]+.
[00214] Example 62. 1-(1-
acryloylpiperidin-3-yI)-4-amino-3-(4-(3-
fluorophenoxy)phenyI)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
O*
NH2 ilk
N
HN N
62
0
[00215] The title compound was made was made from racemic le and intermediate
5
via the similar conditions described in steps 10-1G of Example 1. MS (ESI):
m/z = 474
[M+H]+.
[00216] Example 63. 4-amino-141-[(E)-4-(dimethylamino)but-2-enoy1]-3-
piperidy11-3-
[4-(3-fluorophenoxy)phenyl]-6H-pyrrolo[2,3-d]pyridazin-7-one
OQ
NH2
1\1""
I
HN
0

63 tN-1(-/---N\
0
SUBSTITUTE SHEET (RULE 26)

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[00217] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 62) via the similar conditions
described
in step 16C of Example 16. MS (ESI): m/z = 531 [M+H]+.
[00218] Example 64. 1-(1-
acryloylpiperidin-3-yI)-4-amino-3-(4-(4-
chlorophenoxy)phenyI)-1 H-pyrrolo[2,3-d]pyridazi n-7(6 H )-one
Ci
NH2
N
HN
0
0
[00219] The title compound was made was made from racemic le and intermediate
3
via the similar conditions described in steps 1D-1G of Example 1. MS (ESI):
m/z =490
[M+H].
[00220] Example 65. 4-amino-344-
(4-chlorophenoxy)pheny1]-141-[(E)-4-
(dimethylamino)but-2-enoy1]-3-piperidy1]-6H-pyrrolo[2,3-d]pyridazin-7-one
0
NH2
HN N \
N
065 tN
0
[00221] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 64) via the similar conditions
described
in step 16C of Example 16. MS (ESI): m/z = 547 [M-'-H].
[00222] Example 66. 1-(1-
acryloylpiperidin-3-yI)-4-amino-3-(4-(3-
chlorophenoxy)phenyI)-1 H-pyrrolo[2,3-d]pyridazi n-7(6 H )-one
SUBSTITUTE SHEET (RULE 26)

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0*
NH2 CI
49
N
I\
HN
0
66
0
[00223] The title compound was made was made from racemic le and intermediate
6
via the similar conditions described in steps 1D-1G of Example 1. MS (ESI):
m/z = 490
[M+H]+.
[00224] Example 67. 4-amino-3-[4-(3-
chlorophenoxy)pheny1]-1-[1-[(E)-4-
(dimethylamino)but-2-enoy1]-3-piperidy1]-6H-pyrrolo[2,3-d]pyridazin-7-one
0*
CI
NH2
N
I
HN
0
67
0
[00225] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 66) via the similar conditions
described
in step 16C of Example 16. MS (ES!): m/z = 547 [M-FH]+.
[00226] Example 68. 1-(1-acryloylpiperidin-3-y1)-
4-amino-3-(4-(3-chlorophenoxy)-3-
methoxypheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
/ 0
0
NH2 CI
4.
r- \
HN
0
68 o
0
SUBSTITUTE SHEET (RULE 26)

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[00227] The title compound was made was made from racemic le and intermediate
7
via the similar conditions described in steps 1D-1G of Example 1. MS (ESI):
m/z = 520
[M+H]+.
[00228] Example 69. 4-amino-344-(3-chlorophenoxy)-3-methoxy-phenyl]-141-[(E)-4-

(dimethylamino)but-2-enoy1]-3-piperidy1]-6H-pyrrolo[2,3-d]pyridazin-7-one
0
NH2 CI
N
I
HN
0
69
0
[00229] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 68) via the similar conditions
described
in step 16C of Example 16. MS (ESI): m/z = 577 [M-'-H].
[00230] Example 70. (R)-1-(1-acryloylpiperidin-3-
yI)-4-amino-3-(4-(2-
chlorophenoxy)phenyI)-1 H-pyrrolo[2,3-d]pyridazi n-7(6 H )-one
ci
0 40,
NH2.
N
I
HN
0
of

[00231] The title compound was made was made from le and intermediate 10 via
the
similar conditions described in Example 58. MS (ESI): m/z = 490 [M4-H].
[00232] Example 71. 4-amino-344-(2-
chlorophenoxy)pheny1]-1-[(3R)-1-[(E)-4-
(dimethylamino)but-2-enoyI]-3-piperidy1]-6H-pyrrolo[2,3-d]pyridazin-7-one
SUBSTITUTE SHEET (RULE 26)

CA 02953798 2016-12-23
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- 48 -
ci
o
NH2 40
N
I
HN
071 oN
[00233] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 70) via the similar conditions
described
in step 16C of Example 16. MS (ES1): m/z = 547 [M+H]+.
[00234] Example 72. (R)-1-(1-acryloylpiperidin-3-y1)-4-amino-3-(4-(3,4-
dichlorophenoxy)-3-methoxypheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
CI
0
NH2 CI
410
N \
HN
0
72
[00235] The title compound was made was made from le and intermediate 8 via
the
similar conditions described in Example 58. MS (ES1): m/z = 554 [M+H].
[00236] Example 73. 4-amino-344-(3,4-dichlorophenoxy)-3-methoxy-pheny1]-1-
[(3R)-
1-[(E)-4-(dimethylamino)but-2-enoy1]-3-piperidy1]-6H-pyrrolo[2,3-d]pyridazin-7-
one
CI
0
CI
NH2
N \
HN
0

73 oN-1-/--
0
SUBSTITUTE SHEET (RULE 26)

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[00237] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 72) via the similar conditions
described
in step 16C of Example 16. MS (ES1): m/z = 611 [M+H]+.
[00238] Example 74. (R)-1-(1-
acryloylpiperidin-3-y1)-4-amino-3-(3-fluoro-4-
phenoxypheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
*
NH2
\
HN
0
74
0
[00239] The title compound was made from le and intermediate 12 via the
similar
conditions described in Example 58. MS (ES1): m/z = 474 [M+H].
[00240] Example 75. 4-amino-1-
[(3R)-1-[(E)-4-(dimethylamino)but-2-enoy1]-3-
piperidy1]-3-(3-fluoro-4-phenoxy-pheny1)-6H-pyrrolo[2,3-d]pyridazin-7-one
*
NH2
N
I
HN
0
LN
[00241] The title compound was made from (E)-4-(dimethylamino) but-2-enoic
acid
and corresponding amine (precursor of example 74) via the similar conditions
described
in step 16C of Example 16. MS (ES1): m/z = 531 [M-'-H].
[00242] Example 76. (R)-1-(1-
acryloylpiperidin-3-y1)-4-amino-3-(2-fluoro-4-
phenoxypheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
SUBSTITUTE SHEET (RULE 26)

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0*
NH2
N
I\
HN
0
76
0
[00243] The title compound was made from le and intermediate 11 via the
similar
conditions described in Example 58. MS (ES1): m/z = 474 [M+H].
[00244] Example 77. 4-amino-1-[(3R)-1-[(E)-4-(dimethylamino)but-2-enoy1]-
3-
piperidy1]-3-(2-fluoro-4-phenoxy-pheny1)-6H-pyrrolo[2,3-d]pyridazin-7-one
0*
N,2 41,
N \
HN
0
77
0
[00245] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 76) via the similar conditions
described
in step 16C of Example 16. MS (ES1): m/z = 531 [M-FH]+.
[00246] Example 78. (R)-1-(1-acryloylpiperidin-3-y1)-4-amino-3-(4-(2-
chloro-6-
fluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
Ci
0
NH2 F
N \
HN
0
78
0
SUBSTITUTE SHEET (RULE 26)

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[00247] The title compound was made from le and intermediate 9 via the similar
conditions described in Example 58. MS (ESI): m/z = 508 [M+H].
[00248] Example 79. 4-amino-3-[4-(2-chloro-6-fluoro-phenoxy)phenyI]-1-[(3R)-1-
[(E)-
4-(dimethylamino)but-2-enoy1]-3-piperidy1]-6H-pyrrolo[2,3-d]pyridazin-7-one
0
NH2 4i
N
I
HN
0
79 0
[00249] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 78) via the similar conditions
described
in step 16C of Example 16. MS (ESI): m/z = 565 [M+H]+.
[00250] Example 80. (R)-1-(1-acryloylpiperidin-3-y1)-4-amino-2-chloro-3-
(4-
phenoxypheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
0= 0 = 0*
NH2 NH2 ijks NH2 lks
N
I NCS
N 1) HCI
N
HN I CI I CI
HN
2) K2003 HN
0
0 0
1h oNBcc A
80a tNB0c B 0
0
Step 80A
[00251] A mixture of lh (23 mg) and NCS (15 mg) in DCM (1.5 ml) was stirred at
rt for
20 h and concentrated. The residue was purified by silica gel chromatography
to afford
beige solid 80a (13 mg). MS (ESI): m/z = 536 [M+H]+.
Step 80B
[00252] A mixture of 80a (13 mg) and HCI solution (0.2 ml, 4M in dioxane) in
DCM (1
ml) was stirred at rt for 0.5 h and concentrated. The crude product was
dissolved in THE
SUBSTITUTE SHEET (RULE 26)

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and cooled in ice bath. To the mixture was added K2CO3 (2 M, 30 pl) and a
solution of
acryloyl chloride (5 mg) in THF. The resulting mixture was stirred at 0 C for
30 min and
purified by reversed phase preparative HPLC to give title compound 80 (2.1 mg)
as off
white solid. MS (ES1): m/z = 490 [M+H].
[00253] Example 81. (R)-1-(1-
acryloylpiperidin-3-y1)-4-amino-2-fluoro-3-(4-
phenoxypheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
0*
NH2
N' \
F
HN
081
0
[00254] A mixture of lg (120 mg, 0.23 mmol) and selectflour (98.9 mg, 0.28
mmol) in
CH3CN (10 ml) was refluxed for 10h. After cooled to room temperature, the
solvents
were removed. Water was added, the mixture was extracted with Et0Ac three
times.
The combined organic extracts were washed with water, brine, dried over MgSO4,

filtered, and concentrated to give oil 81a (71 mg). MS (ES1): m/z = 534
[M+H]+.
[00255] The title compound was made from 81a and via the similar conditions
described in steps 1E-1G of Example 1. MS (ES1): m/z = 474 [M+H]+.
[00256] Example 82. 4-amino-1-
[(3R)-1-[(E)-4-(dimethylamino)but-2-enoy1]-3-
piperidy1]-2-fluoro-3-(4-phenoxypheny1)-6H-pyrrolo[2,3-d]pyridazin-7-one
*
NH2 =
N ,
I F
HN
o82 LN
0
[00257] The title compound was made from (E)-4-(dimethylamino)but-2-enoic acid

and corresponding amine (precursor of example 81) via the similar conditions
described
in step 160 of Example 16. MS (ES1): m/z = 531 [M+H].
SUBSTITUTE SHEET (RULE 26)

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[00258] Example 83. (R)-1-(1-
acryloylpiperidin-3-y1)-4-amino-2-chloro-3-(4-(2-
fluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
0*
F
NH2 irkt
N
CI
HN
083
tN
[00259] The title compound was prepared via the similar conditions described
in
Example 80. MS (ES1): m/z=508 [M+H].
[00260] Example 84. (R)-3-(4-
amino-3-(4-(2,6-difluorophenoxy)pheny1)-7-oxo-6,7-
dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)piperidine-1-carbonitrile
0 411t
NH2 = F
r I \
HN
0
8 o
4N-CN
[00261] The title compound was prepared via the similar conditions described
in
Example 20. MS (ES1): m/z=463 [M+H]+.
[00262] Example 85. (R)-3-(4-amino-3-(3-fluoro-4-phenoxypheny1)-7-oxo-6,7-
dihydro-
1H-pyrrolo[2,3-d]pyridazin-1-yl)piperidine-1-carbonitrile
*
NH2
I I
HN
0
85 N CN
SUBSTITUTE SHEET (RULE 26)

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[00263] The title compound was prepared via the similar conditions described
in
Example 20. MS (ESI): m/z=445 [M+H].
[00264] Example 86. (R)-3-(4-
amino-2-chloro-3-(4-(2-fluorophenoxy)phenyI)-7-oxo-
6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)piperidine-1-carbonitrile
0
F
NH2
N
I I CI
HN
0
86 LN-cN
[00265] The title compound was prepared via the similar conditions described
in
Example 20, 80. MS (ESI): m/z=479 [M+H].
[00266] Example 87. (R)-3-(4-
amino-3-(4-(2-fluorophenoxy)phenyI)-7-oxo-6,7-
dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)piperidine-1-carbonitrile
0
F
NH2 fik
N
I I
HN
0
87 N-.cN
[00267] The title compound was prepared via the similar conditions described
in
Example 20. MS (ESI): m/z=445 [M+H].
[00268] Example 88. N-(3-(4-
amino-7-oxo-3-(4-phenoxyphenyI)-6,7-dihydro-1H-
pyrrolo[2,3-d]pyridazin-1-yl)phenyl)acrylamide
SUBSTITUTE SHEET (RULE 26)

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(H0)2B
Br
CN OH NC Br
EtO2C1-.
CO Et NH3' Et0Ac. Br2 88NHBoc NC
c
2 Reflux Et02e"¨N
OH CN EtO2C cHci3
EtO2C cu(0A02
lb A 88a B 88b C 88d NH
I3oc
4111k 0*
0 0
40 0
NH2
lf B(01-1)2 NH2 1 ) HCI
H2NNH2
____________________________________________________ N \
Pd(dppf)C12, Na2CO3 NC ,
' Et0H,reflu; 2) K2CO3 HA N
dioxane, 80 C N N N
EtO2C 0 0
88e NHBoc
C8)8f ift NHBoco F
88 NI
*
Step 88A
[00269] To a solution of lb (1.62 g) in Et0Ac (30 ml) at 60 C was added
dropwise a
solution of 0.5 M NH3 in dioxane (22 ml). The mixture was refluxed for 18 h.
After cooled
to room temperature, the solvents were removed. The residue was purified by
silica gel
chromatography to afford light yellow solid 88a (0.37 g).
Step 88B
[00270] To a solution of 88a (320 mg) in 0HCI3 (17 ml) at -20 C was added
dropwise
a solution of Br2 (350 mg) in CHCI3 (3 ml). The mixture was stirred at lower
than 10 C for
h, and then quenched with a solution of 10% Na2S203 and saturated solution of
NaHCO3. The two phases were separated; the aqueous phase was extracted with
DCM
three times. The combined organic layers were dried over Na2SO4, filtered and
concentrated. The residue was purified by silica gel chromatography to give
88b (400
mg).
Step 88C
[00271] To a mixture of 88b (200 mg, 0.82 mmol), 88c (390 mg, 1.64 mmol) in
DCM
(10 ml) at 0 C was added Cu(OAc)2 (224 mg, 1.23 mmol) and pyridine (185 pl).
The
mixture stirred at rt for 20h. Water was added, extracted with Et0Ac twice.
The organic
extracts were washed with brine, dried over Na2SO4, filtered, and
concentrated. The
residue was purified by silica gel chromatography to give 88d (360 mg).
SUBSTITUTE SHEET (RULE 26)

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Step 880
[00272] A mixture of 88d (133 mg, 0.306 mmol), If (131 mg, 0.612 mmol), K2003
(2M,
0.5 ml), and Pd(dppf)Cl2 (49 mg, 0.06 mmol) in 1.4-dioxane(8 ml) was stirred
in under
N2 at 80 C for 18 h. Water was added, extracted with Et0Ac twice. The organic
extracts were washed with brine, dried over Na2SO4, filtered, and
concentrated. The
residue was purified by silica gel chromatography to give colorless oil 88e
(135 mg). MS
(ESI): m/z=524 [M+H].
Step 88E
[00273] A mixture of 88e (130 mg) and N2H4 (1.2 ml) in Et0H (10 ml) was
refluxed for
24 h. After cooled to room temperature, the solvents were removed. The residue
was
purified by silica gel chromatography to give white solid 88f (38 mg). MS
(ESI):
m/z=510 [M+H].
Step 88F
[00274] A mixture of 88f (18 mg) and HCI solution (1 ml, 4 M in dioxane) was
stirred at
rt for 1 h and concentrated. The crude product was dissolved in THF and cooled
in ice
bath. To the mixture was added K2CO3 (2 M, 40 pl) and a solution of acryloyl
chloride (4
mg) in THF. The resulting mixture was stirred at 0 C for 20 min and purified
by reversed
phase preparative HPLC to give title compound 88 (7.2 mg) as white solid. MS
(ESI):
m/z = 464 [M+H]+.
[00275] Example 89. N-(3-(4-amino-3-(3-chloro-4-methoxypheny1)-7-oxo-6,7-
dihydro-
1H-pyrrolo[2,3-d]pyridazin-1-yl)phenyl)acrylamide
0¨

ipCI
NH2 wir
N
I I
HN
0
089
[00276] The title compound was made from 88d and (3-chloro-4-
methoxyphenyl)boronic acid via the similar conditions described in steps 88D-
88F of
Example 88. MS (ESI): m/z = 436 [M+H].
[00277] Example 90. N-(4-(4-amino-7-oxo-3-(4-phenoxyphenyI)-6,7-dihydro-1H-
SUBSTITUTE SHEET (RULE 26)

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pyrrolo[2,3-d]pyridazin-1-yl)phenyl)acrylamide
0*
NH2
r I \
HN
0
0
[00278] The title compound was made from 88b and (4-((tert-
butoxycarbonyl)amino)phenyl)boronic acid via the similar conditions described
in steps
88C-88F of Example 88. MS (ESI): m/z = 464 [M+H].
[00279] Example 91. N-(3-(4-amino-3-(4-(2-fluorophenoxy)phenyI)-7-oxo-6, 7-d
ihyd ro-
1H-pyrrolo[2,3-d]pyridazin-1-yl)phenyl)acrylamide
*
F
NH2
I I
HN
0
91
0 NL
[00280] The title compound was made from 88d and (4-(2-
fluorophenoxy)phenyl)boronic acid via the similar conditions described in
steps
88D-88F of Example 88. MS (ESI): m/z = 482 [M+H]+.
[00281] Example 92. (E)-N-[3-[4-amino-3-[4-(2-fluorophenoxy)phenyI]-7-oxo-
6H-
pyrrolo[2,3-d]pyridazin-1-yl]phenyI]-4-(dimethylamino)but-2-enamide
SUBSTITUTE SHEET (RULE 26)

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F
0 =0
0
OF
NH2 W NH2
N
I I N
I
HN
HN
0 N,
0
9 2a = 92 411 N
N H2
[00282] To a solution of 92a (10mg) in DCM at 0 C was added fresh prepared (E)-
4-
(dimethylamino)but-2-enoyl chloride. The resulting mixture was stirred at 0 C
for 0.5 h
and purified by reversed phase preparative HPLC to give title compound 92 (1
mg). MS
(ESI): m/z = 539 [M+1-1] +.
[00283] Example 93. (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-y1)-3-(4-
(2,6-
difluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
H2N CN CN
CN OH EtO2C CO2Et Et0Ac .A¨0O2Et
Et Pd2(dba)3, P(CY)3
¨0O2
,
_____________________________ ¨N Br2
N dioxane, reflux
, reflux
OH CN 12
lb A oNBoc
93a B .1R1Boc
93b
= F 41k, F
0 0
tio 0
CN
N2H4 NH2 1) TEA NH2
I CO2Et
Et0H,reflux NJ I \ 2) EDCI N1' \
HN N HO -- HN N
93c D 0 0
93d --1NBoc 0 E
93 -11\1%
0
Step 93A
[00284] To a solution of lb (1.5 g) in Et0Ac (84 ml) at 60 C was added
dropwise a
solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.41 g) in Et0Ac
(21 ml). The
mixture was refluxed for 4 h. After cooled to room temperature, the solvents
were
removed. The residue was purified by silica gel chromatography to afford 93a
(0.686 g).
SUBSTITUTE SHEET (RULE 26)

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Step 93B
[00285] To a solution of 93a (0.686 g) in DCM (120 ml) at 0 C was added slowly
a
solution of Br2 (3.7 g) in DCM (5 m1). The mixture was stirred for 1.5 h, and
then
quenched with a solution of 10% Na2S203 and saturated solution of NaHCO3. The
two
phases were separated; the aqueous phase was extracted with DCM. The combined
organic extracts were treated with excess Boc20, dried over Na2SO4, filtered
and
concentrated. The residue was purified by silica gel chromatography to give
93b (0.342
9).
Step 93C
[00286] A mixture of 93b (198 mg, 0.48 mmol), 12 (160 mg, 0.48 mmol) and
K3PO4=3H20 (188 mg, 0.72 mmol) in 1.4-dioxane/water (10 m1/1 ml) was degassed
with
N2. Next was added Pd2(dba)3 (22 mg, 0.024 mmol) and P(Cy)3 (14 mg, 0.048
mmol).
The resulting mixture was refluxed under N2 for 16 h. After cooled to room
temperature,
the solid was filtered off, the filtrate was concentrated. The residue was
purified by silica
gel chromatography to give white solid 93c (59 mg). MS (ES1): m/z=538
Step 930
[00287] A mixture of 93c (72 mg, 0.13 mmol) and N2H4.1-120 (1 mL) in Et0H (5
ml)
was refluxed for 16 h. After cooled to room temperature, the solvents were
removed.
The residue was purified by silica gel chromatography to give white solid 93d
(24 mg).
MS (ES1): m/z=524 [M+H].
Step 93E
[00288] To a solution of 93d (40 mg, 0.08 mmol) in DCM (5 ml) was added TFA (1
ml).
The mixture was stirred at it for 3 h and concentrated to give oil 93e (49
mg). To a
solution of 93e (49 mg) in DCM (5 ml) was added but-2-ynoic acid (13 mg, 0.16
mmol),
EDCI (31 mg, 0.16 mmol) and TEA (17 mg, 0.16 mmol). The resulting mixture was
stirred at room temperature for 18 h and concentrated. The residue was
purified by silica
gel chromatography to give the title compound 93 (20 mg) as white solid. MS
(ES1):
m/z = 490 [M+H] +.
[00289] Example 94. (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-y1)-3-(4-(2-
chloro-6-
fluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
SUBSTITUTE SHEET (RULE 26)

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'CI
0
NH2 *
N
HN
Oh
94
0
[00290] The title compound was made from 93b and intermediate 9 via the
similar
conditions described in steps 93C-93E of Example 93. MS (ESI): m/z = 506
[M+H]+.
[00291] Example 95. (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yI)-3-(4-
(2-
fluorophenoxy)phenyI)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
=
0
NH2
NI
HN
0
0
[00292] The title compound was made from 93b and ((4-(2-
fluorophenoxy)phenyl)boronic acid via the similar conditions described in
steps
93C-93E of Example 93. MS (ESI): m/z = 472 [M+H]+.
[00293] Example 96. (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yI)-3-(4-
(2-
chlorophenoxy)phenyI)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
SUBSTITUTE SHEET (RULE 26)

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*
CI
NH2
HN N
096
0
[00294] The title compound was made from 93b and intermediate 10 via the
similar
conditions described in steps 93C-93E of Example 93. MS (ES1): m/z = 488
[M+H]+.
[00295] Example 97. (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-y1)-3-
(4-
phenoxypheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
41kt
0
NH2
\
HN N
097
0
[00296] The title compound was made from 93b and (4-phenoxyphenyl)boronic acid

via the similar conditions described in steps 930-93E of Example 93. MS (ES1):
m/z =
454 [M+H]+.
[00297] Example 98. 4-amino-1-((3S,4S)-1-(but-2-ynoy1)-4-methoxypyrrolidin-3-
y1)-3-
(4-(2-fluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one and
enantiomer
SUBSTITUTE SHEET (RULE 26)

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0
NH2 410
N"
HN
0
98
0
[00298] The title compound was made from trans-tert-butyl 3-amino-4-
methoxypyrrolidine-1-carboxylate via the similar conditions described in
Example 1. MS
(ESI): m/z=502 [M+H].
[00299] Example 99. (R)-4-amino-1-(1-(4-(dimethylamino)but-2-ynoyOpyrrolidin-3-
y1)-
3-(4-(2-fluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
= F
0
NH2
N
HN
0
99
0
[00300] The title compound was prepared via the similar procedures described
in
Example 93. MS (ES1): m/z=515 [M+H].
[00301] Example 100. N-(3-(4-amino-3-(4-(2-fluorophenoxy)phenyI)-7-oxo-6,7-

dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)cyclopentyl)but-2-ynamide
SUBSTITUTE SHEET (RULE 26)

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F
0
NH2 *
N
HN
0 oN 0
100
[00302] The title compound was prepared via the similar procedures described
in
Example 93. MS (ESI): m/z=486 [M+H].
[00303] Example 101. (S)-4-amino-
1-(1-(but-2-ynoyl)pyrrolidin-3-y1)-3-(4-(2-
fluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
=
0
NH2
N
HN
0
0
[00304] The title compound was prepared via the similar procedures described
in
Example 93. MS (ESI): m/z=472 [M+H].
[00305] Example 102. N-((1s,45)-
4-(4-amino-3-(4-(2-fluorophenoxy)pheny1)-7-oxo-
6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)cyclohexyl)but-2-ynamide
SUBSTITUTE SHEET (RULE 26)

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F
0
NH2 *
N
I I
HN
0 t_?102 ,
HN
0
[00306] The title compound was prepared via the similar procedures described
in
Example 1. MS (ESI): m/z=500 [M+H].
[00307] Example 103. N-((1 r,4 r)-4-(4-am no-3-(4-(2-fluorophenoxy)ph eny1)-7-
oxo-6,7-
d ihyd ro-1H-pyrrolo[2,3-d]pyridazin-1-y1 )cyclohexyl)but-2-ynam id e
41k, F
0
NH2
I \
HN
0 o
103 H
0
[00308] The title compound was prepared via the similar procedures described
in
Example 1. MS (ESI): m/z=500 [M-4-H].
[00309] Example 104. N-((1s,4s)-4-(4-amino-3-(4-(2-fluorophenoxy)phenyI)-7-
oxo-
6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)cyclohexyl)acrylamide
SUBSTITUTE SHEET (RULE 26)

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gip F
0
NH2 at
N
HN
0104
HN-
[00310] The title compound was prepared via the similar procedures described
in
Example 1. MS (ES1): m/z=488 [M-4-H].
[00311] Example 105. N-((1r,4 r)-4-(4-ami no-3-(4-(2-fluorophenoxy)pheny1)-7-
oxo-6,7-
d ihyd ro-1 H-pyrrolo[2,3-d]pyridazin-1-yl)cyclohexyl)acrylamide
410 F
0
NH2
Y' \
HN
Do
105
0
[00312] The title compound was prepared via the similar procedures described
in
Example 1. MS (ES1): m/z=488 [M-4-H].
[00313] Example 106. (R)-1-(1-acryloylpyrrolidin-3-y1)-4-amino-3-(4-
(2-
fluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
SUBSTITUTE SHEET (RULE 26)

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F
0
NH2
N
I I
HN
0
106
0
[00314] The title compound was prepared via the similar procedures described
in
Example 1. MS (ESI): m/z=460 [M+H].
[00315] Example 107. (R)-3-(4-amino-7-oxo-3-(4-phenoxyphenyI)-6,7-dihydro-
1H-
pyrrolo[2,3-d]pyridazin-1-yl)pyrrolidine-1-carbonitrile
0Q
NH2
HN
0
107 o,
CN
[00316] The title compound was prepared via the similar conditions described
in
Example 20. MS (ESI): m/z=413 [M+H].
[00317] Example 108. 3-(4-amino-3-(4-(2-fluorophenoxy)pheny1)-7-oxo-6,7-
dihydro-
1H-pyrrolo[2,3-d]pyridazin-1-yOpiperidine-1-carbonitrile
0=
F
NH2 *
N
HN
0
108 ol-CN
[00318] The title compound was prepared via the similar conditions described
in
Example 20. MS (ESI): m/z=445 [M+H].
SUBSTITUTE SHEET (RULE 26)

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[00319] Example 109. (R)-1-(1-acryloylpiperidin-3-yI)-4-amino-3-(4-
(2-
fluorophenoxy)phenyI)-1H-pyrazolo[3,4-d]pyridazin-7(6H)-one
OH
6'0H
Br
Br
NC NC J 40
Br2, NaOH NC \ N DIAD, PP%. I .11 0 109d
Et0 dioxane/H20Et0 N THF, 0 C-RTEt0 N Pd(dppf)C12, K2CO3
0 o B0 dioxane. 85 C
109a A
109b 109c N-Boc
0 e 0 = 0
NH2 NH2
NC N2I-14 1) HCI
N' N'
N
kiN Me0H,reflux HN N' 2) HATU HN
EtO2C "
0H00
109e aNBoc D 109f aNBoc 0
109
0
Step 109A
[00320] To a mixture of 109a (200 mg) and NaOH (2 M, 1.2 ml) in dioxane (4 ml)
at
0 C was added a solution of Br2 (380 mg) in dioxane (2 ml). The mixture was
stirred at rt
for 1 h and concentrated. The residue was purified by silica gel
chromatography to give
109b (340 mg).
Step 109B
[00321] To a solution of 109b (50 mg), (S)-tert-butyl 3-hydroxypiperidine-1-
carboxylate
(80 mg) and PPh3 (100 mg) in THE (5 ml) at 0 C was added DIAD (80 mg). The
mixture
was stirred at rt for 18 h and concentrated. The residue was purified by
silica gel
chromatography to give 109c (76 mg).
Step 109C
[00322] A mixture of 109c (70 mg), 109d (114 mg), K2CO3 (113 mg), and
Pd(dppf)C12
(66 mg) in dioxane/water(5 m1/0.5 ml) was stirred in under N2 at 85 C for 3
h. After
cooled to room temperature, the solvents were removed. The residue was
purified by
silica gel chromatography to give 109e (100 mg). MS (ESI): m/z=535 [M+H].
Step 109D
[00323] A mixture of 109e (100 mg) and N2H4 (2.5 ml) in Me0H (5 ml) was
refluxed for
SUBSTITUTE SHEET (RULE 26)

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3 h. After cooled to room temperature, the solvents were removed. The residue
was
purified by silica gel chromatography to give 109f (70 mg). MS (ESI): m/z=521
[M-'-H].
Step 109E
[00324] A mixture of 109f (70 mg) and HCI solution (4 ml, 4M in dioxane) was
stirred
at rt for 0.5h and concentrated to give 109g (100 mg) which was used directly
in next
step.
[00325] To a solution of 109g (9 mg) in DMF (1 ml) was added DIEA (13 mg),
acid (6
mg) and HATU (18 mg). The resulting mixture was stirred at room temperature
for 0.5 h
and purified by reversed phase preparative HPLC to give title compound 109
(3.1 mg).
MS (ESI): tniz = 475 [M+H].
[00326] Example 110. (R)-1-(1-acryloylpiperidin-3-y1)-4-amino-3-(4-
phenoxypheny1)-
1H-pyrazolo[3,4-d]pyridazin-7(6H)-one
0
NH2
N
,N
HN
0
110 LN
0
[00327] The title compound was made was made from 109c and (4-
phenoxyphenyl)boronic acid via the similar conditions described in steps 109C-
109E of
Example 109. MS (ESI): rniz = 457 [M+H].
[00328] Example 111. (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-y1)-3-
(4-
phenoxypheny1)-1H-pyrazolo[3,4-d]pyridazin-7(6H)-one
*
NH2
\ N
HN
0
111
0
SUBSTITUTE SHEET (RULE 26)

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[00329] The title compound was made was made from 109b and proper reagents via

the similar conditions described in steps 109B-109E of Example 109. MS (ESI):
m/z =
455 [M+H].
[00330] Example 112. (R)-4-amino-
1-(1-(but-2-ynoyl)pyrrolidin-3-y1)-3-(4-(2-
fluorophenoxy)phenyI)-1H-pyrazolo[3,4-d]pyridazin-7(6H)-one
0 e
NH2HN
N \ N
N'
0
112
0
[00331] The title compound was made was made from 109b and proper reagents via

the similar conditions described in steps 109B-109E of Example 109. MS (ESI):
m/z =
473 [M-FH]+.
[00332] Example 113. (R)-4-amino-
1-(1-(but-2-ynoyl)pyrrolidin-3-y1)-3-(4-(2,6-
difluorophenoxy)pheny1)-1H-pyrazolo[3,4-d]pyridazin-7(6H)-one
0 4Ik
NH2 F
\
HN
0
113
0
[00333] The title compound was made was made from 109b and proper reagents via

the similar conditions described in steps 109B-109E of Example 109. MS (ESI):
m/z =
491 [M+H].
[00334] Example 114. (S)-1-(1-
acryloylpiperidin-3-yI)-4-amino-3-(4-(2,6-
difluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
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F
0 =
NH2 F
HN
0
114 0
[00335] The title compound was prepared via the similar conditions described
in
Example 58. MS (ESI): m/z = 492 [M+1-1]+.
[00336] Example 115. (R)-4-amino-3-(4-(2,6-difluorophenoxy)pheny1)-1-(1-

propionylpiperidin-3-y1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
0 =
NH2
\
HN
0
115 0
[00337] The title compound was prepared from compound 58 via the similar
conditions described in Example 19. MS (ESI): m/z = 494 [M-+I].
[00338] Example 116. 4-amino-344-(2,6-difluorophenoxy)pheny1]-1-[(3R)-1-[(E)-
but-2-
enoy1]-3-piperidy1]-6H-pyrrolo[2,3-d]pyridazin-7-one
0 =
NH2 F
r I \
HN
0
oN
116 0
SUBSTITUTE SHEET (RULE 26)

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[00339] The title compound was made from (E)-but-2-enoic acid and amine 58c
via
the similar conditions described in step 58C of Example 58. MS (ESI): m/z =
506
[M+H]+.
[00340] Example 117. (R)-4-amino-
1-(1-(but-2-ynoyl)piperidin-3-y1)-3-(4-(2,6-
difluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
0
NH2 F
N \
HN I N
0
N/
o
117 0
[00341] The title compound was made from but-2-ynoic acid and amine 58c via
the
similar conditions described in step 580 of Example 58. MS (ESI): m/z = 504
[M+H].
[00342] Example 118. (R)-4-amino-
1-(1-butyrylpyrrolidin-3-y1)-3-(4-(2,6-
difluorophenoxy)pheny1)-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one
F
0
NH2 fk
N \
FIN I N
0
118
0
[00343] The title compound was prepared compound 93 via the similar conditions
described in Example 19. MS (ESI): m/z = 494 [M+H].
[00344] Example 119. Evaluation of BTK activity
[00345] Methods for biochemical and cell-based assays:
[00346] Btk kinase assay - The Btk kinase assay was performed using a ADP-Glo
Btk kinase assay kit purchased from Promega (Madison, WI). The assay was
conducted
according to the protocols provided in the assay kit. In brief, the enzyme
reaction was
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carried out in the kinase reaction buffer containing Btk (2 ng/pl), ATP (1.2
pM), poly GT
peptide (0.3 pM), OTT (40 nM), MnC12 (1.4 mM), and lxkinase buffer (included
in the kit)
in the presence or absence of the tested articles at various concentrations in
384-well
plate at room temperature (22 1 C) for 60 minutes. The final reaction
volume for each
reaction was 10 pl. Then, 4 pl of ADP-Glo reagent (included in the kit) was
added into
the reaction and the plate was further incubated for another 40 minutes to
terminate the
reaction and deplete the remaining ATP. Finally, 10 pl of the kinase detection
reagent
was added into each reaction to simultaneously convert ADP to ATP and allow
the
newly synthesized ATP to be measured by a plate-reading luminometer (Victor X5
2030
multilabel reader, PerkinElmer). IC50 value was calculated using appropriate
programs
in Graph Pad Prism by plotting the logarithm of the concentration versus
percent
inhibition as compared with a vehicle (DMSO) control. The IC50 values for the
example
compounds are shown in Table 4.
[00347] Cell proliferation assay: TMD-8 and SU-DHL-1 cells were maintained at
37 C in a humidified atmosphere with 5% CO2 in the recommended medium and
serum
concentrations. For cell proliferation assay, cells were seeded in 96-well
pates at a
density of 5,000 to 10,000 cells per well and cultured overnight at 37 C in
recommended
medium supplemented with 5-10% FBS. On the next day, the test articles at
various
concentrations or vehicle control (0.5% DMSO) were added into cell culture.
After 5-day
treatment, the growth of cells was assayed by the CellTiter-Glo
Luminestceaent Cell
Viability Assay (Promega). IC50 values were calculated using GraphPad Prism by

plotting the logarithm of the concentration versus percent inhibition of cell
growth as
compared with the vehicle control. The 1050 values for the example compounds
are
shown in Table 4.
Table 4. Biological Testing Results
[00348] A 0.01 pM; 0.01 pM < B pM; 1 pM < C< 100 pM
BTK 'ëi9MëTCTMD8 cells droWthr-
]Fxample
1 A A
2 A A
3
4
6 B A
7
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BTK erizyme . .--r-:';1:-..=:'-'.-
c,,0 TMD8 cells grovAit 1
]'Example
(PM):::: .. ..::g:::.. 'Cho (pM):::,:::,::::::::::.:::g!
8 B B
9 C -
B B
11 B A
12 B A
13 A A
14 A A
_ B A
16 A B
17 B B
18 A A
19 B B
B _ A
21 C -
22 B B
23 B B
24 B B
B B
26 A A
27 A A
28 A A
29 B A
B B
31 A _ B
32 B B
33 A A
34 A A
A A
36 A B
37 _ C -
38 A A
39 A A
B B
41 B B
42 C -
43 B B
44 B B
A A
46 B B
47 A A
48 B B
49 B B
B B
51 A B
52 A C
53 A _ B
54 A B
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. .......... .............,
BTK erizyme 10:.;o= TMD8 cells grovAit I
Mxample
(PM):::: .. ..::g:::.. 'Cho (pM):::,:::,............:]]]]]].1!
55 A A
56 A A
57 A A
58 A A
59 B A
60 B B
61 B B
62 _ B A
63 A A
64 B A
65 B B
66 B A
67 A _ B
68 B A
69 A A
70 B A
71 A A
72 B B
73 B B
74 B A
75 A B
76 B A
77 A A
78 A _ A
79 A A
80 B B
81 B A
82 A A
83 C -
84 _ B A
85 B A
86 C -
87 A A
88 A A
89 B B
90 B A
91 B A
92 B A
93 B A
94 B A
95 B A
96 B B
97 B A
98 B B
99 A B
100 B _ A
101 C
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xample BTK erizyMe-ICK6'''TMD8 cells grovAhlf":"1
.. ICho(pM)
102 B A
103 B A
104 B A
105
106 B A
107 A
108 A A
109 B A
110 B A
111 A A
112 B A
113 B A
114 B A
115
116
117
118
[00349] Pharmacokinetic tests: The tested articles were given to Sprague-
Dawley
rats or Beagle dogs by intravenous and oral administration. Plasma samples
were
prepared from blood samples which were collected at various time points. The
plasma
concentrations of the tested articles were determined by specific LC-MS/MS
analytical
methods. Pharmacokinetic parameters were calculated with WinNonline. The
pharmacokinetic test results for the example compounds are shown in Table 5
(rat) and
Table 6 (dog) below.
Table 5. Rat PK parameters of selected examples.
Example 58 93
Dose IV(0.5mg/kg) PO (5mg/kg) IV (0.5mg/kg) PO (5mg/kg)
Cmax(ng/m1) 1509 1297 710 914
AUC 0-t 1511 6837 395 2290
(ng/ml*h)
t1/2(h) 0.64 4.09 0.63 4.62
CLz/F 5.45 11.0 22.9 39.2
(ml/min/kg)
Vz/F(ml/kg) 301 3827 1371 15421
F% 51.9% 58.1%
Table 6. Dog PK parameters of selected examples.
Example 58 93
Dose IV(0.2mg/kg) PO (2mg/kg) IV (0.5mg/kg) PO (2mg/kg)
Cmax(ng/m1) 145 656 212 315
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AUC 0-t 94.4 1094 525 1290
(ng/ml*h)
t1/2(h) 0.43 0.66 1.5 1.78
CLz/F 35.4 31.1 15.9 26.3
(ml/min/kg)
Vz/F(m I/kg) 1281 1753 2050 4010
F% 114% 61.6%
[00350] In vivo efficacy study: The in vivo antitumor activity was assessed
with
TMD-8 xenograft model. In brief, TMD-8 cells were implanted into NOD-SCID nude

mice and allowed to grow to the designated size (c.a. 100-200 mm3) before
treatment.
The tested articles were given orally at various dose levels once daily (OD)
or twice a
day (BID) for 14 consecutive days. Tumor and body weight were measured during
the
experiments, and tumor volumes were estimated from the formula [length/2] x
[width2].
Established tumors in each animal were individually normalized to their size
at the start
of the experiment, and the data were calculated as the change in tumor volume
relative
to the day 0 volume by the use of the relative tumor volume (RTV) formula,
RTV=TV5/TV0, where TVõ is the tumor volume on any day and TV0 is the tumor
volume
at the initiation of dosing. Significant suppression of tumor growth was
observed with
examples 58 (98% tumor growth inhibition rate) and 93(80% tumor growth
inhibition
rate).
SUBSTITUTE SHEET (RULE 26)